Blood of the innocent
by ILOVEANIME123
Summary: Well... this is gonna be another fail, but Imma try anyway. Just a slight crossover between a couple anime's that I like with Naruto as the base. Pretty much Sasuke goes through a bunch of crap, he's innocent, Itachi's still a caring older brother, and my OC, Uihara Ken, is Sasuke's surrogate older brother. Just read and see how much I failed. Please, constructive criticism only.
1. Chapter 1

Chapter 1

Disclaimer: I do not own Naruto or Deadman Wonderland. I only own my OC's. I've decided to make this fanfiction a slight crossover of a couple different anime's. Naruto is the base for this fanfiction, so the main plot will follow Naruto. I'm just adding my own little twist to it. The anime's I use will be displayed down where the author's notes usually are.

Amegakure, hidden village in the rain. A place where all the civilians were protected from harm by the chakra infused rain. A man walked past the gates of Amegakure carrying the body of a young boy in his teens. The boy had raven hair that stuck out in a duck-like fashion, a dark blue shirt with a large collar, white shorts, and white arm-warmers. The man walked around some more, but stopped when a man with orange hair and ringed purple eyes stepped in front of him.

"State your name and purpose." He ordered. The man smiled and did a small bow.

"My name is Uihara Ken. I am here with Uchiha Sasuke to join the Akatsuki." He said. The ginger's eyes narrowed.

"And why should I allow you to join my organization?" he asked. Ken smiled.

"We have our reasons that we will tell you at a later time, Pein-sama. But for now, let's just say that you would want to have our help." He said. Pein searched the man's eyes for any lies, but found none. Finally, he sighed and nodded.

"Very well. I will allow you to join, but if you try anything suspicious, you will be removed." He said threateningly. Ken smiled again and nodded.

"Arigato, Pein-sama." He said. Pein nodded and motioned him to follow him, leading him to the Akatsuki base. When they went in, Pein called a meeting.

"Everyone, I want you to meet our new members. Uihara Ken and Uchiha Sasuke." He said. Itachi's head snapped up at his brother's name and narrowed his eyes when he saw his baby brother supposedly unconscious in Ken's arms. Hidan saw Sasuke and stared.

"Why the f*ck isn't he awake?" he asked. Ken looked at Sasuke with sad eyes.

"That's the problem right now. He can't wake up even if he wanted to." He said. Kisame stared.

"So he's dead?" he asked. Ken shook his head.

"No, merely in a death like state. He'll wake up soon, I hope." He said, and just as he said that, Sasuke stirred, but kept his eyes shut. Ken saw this and smiled, setting Sasuke on the ground. Sasuke clung to Ken's hand like it was his lifeline and hid behind him. Ken chuckled and patted Sasuke's head.

"Don't be shy, Sasu-chan. Your brother's here, you know?" he said. Sasuke perked up when he heard that his brother was here and squeezed Ken's hand. _Where?_ He asked without saying anything. Ken pulled Sasuke to Itachi and placed Sasuke's hand on Itachi's.

"He's here, Sasu-chan." Ken said softly. Sasuke smiled and hugged Itachi as best as he could, seeing as how short he was. Itachi was shocked by the show of affection as was the rest of the Akatsuki.

"Oi Uchiha, un. Isn't your brother supposed to hate you or something, hmm?" Deidara asked. Itachi nodded.

"He is." He said. Sasuke shook his head and took hold of Ken's hand again.

"He says that he doesn't hate you and that he loves you." Ken said. Itachi looked at Sasuke in shock. Hidan looked at Sasuke with narrowed eyes.

"Why can't the little sh*t speak for himself? And why the f*ck didn't he open his f*cking eyes?!" he asked rudely. Ken sighed as Sasuke tensed.

"He'll tell you when he's ready. Don't pressure him." He said. Hidan made to pressure Sasuke to see what would happen, but he stopped with a glare from Pein. Ken smiled at Itachi and then turned to Pein.

"Should we introduce ourselves?" he asked. Pein nodded.

"Very well. I am Pein and I am the leader of the Akatsuki." He said. The woman next to him smiled.

"I'm Konan and I guess that I'm Pein-sama's co-worker." She said. Ken smiled back at her. Next was the blonde.

"I'm Deidara, un." He said. Next to him was a lump.

"Sasori." It said. Ken looked kind of freaked out, but looked to the religious zealot.

"Hidan. Don't f*cking mess with my religion and we'll get along fine." He said. Ken nodded and looked to the stitched man next to him.

"Kakuzu. Don't touch my money." He said. Then was a plant man.

"I am **Zetsu.** Nice to **meet you.**" He said. Ken nodded and then it was Itachi.

"I am Uchiha Itachi." He said. And finally was the large blue shark man.

"Hoshigaki Kisame. Pleased to make your acquaintance." He said politely. Ken nodded and smiled.

"I'm sure that you know us already, but I am Uihara Ken and he is Uchiha Sasuke." He said, gesturing to himself and the young Uchiha clinging to his hand. Ken leaned down and whispered something to Sasuke, making him turn red and shake his head furiously, giving Ken a very cute pout. Ken just laughed and nodded, pushing him towards Itachi, who just raised an eyebrow.

"What is it?" he asked. Ken chuckled.

"Sasuke has something to tell you, don't you, Sasu-chan?" he said mischievously. Sasuke just blushed more and hesitantly took Itachi's hand in his own. _Nii-san… I missed you._ He said. Itachi jerked back a bit, pulling his hand away from Sasuke, who looked like he was slapped. _'Nii-san hates me?'_ he thought as he walked back to Ken and grabbed his hand again. _Ken-nii, I think that nii-san hates me._ He said. Ken looked down at Sasuke with a sad expression on.

"Why do you say that, Sasu-chan? He was just surprised, that's all. I'm sure that he doesn't hate you." He said. Sasuke turned his head up at Ken, his eyes never opening. _Why would he be surprised?_ He asked.

Ken sighed.

"Well… you don't normally speak into a person's mind." He said. Sasuke nodded. _But there's no other way._ He said. Ken nodded sadly and Pein decided to interrupt there.

"Zetsu will show you to your rooms. We don't have enough, so you'll have to share." He said. Ken nodded and pulled Sasuke along.

"Come on, Sasu-chan. Cheer up. Itachi-san is just surprised that you spoke to him that way." He said. Sasuke nodded and followed Ken and Zetsu to their room. Once they were settled in, Ken pulled Sasuke down to sit on the bed with him.

"Sasu-chan, I know it's hard. Not being able to see or talk. I know that you're in constant pain too. You can tell me anything you want, Sasu-chan." He said. Ruffling Sasuke's hair, making him give a soundless laugh. Sasuke nodded, still smiling. _Arigato, Ken-nii. But you do know that I can talk and see. It's just that if I make a mistake and open my eyes or talk, everyone will die._ He said. Ken nodded.

"I know that, Sasu-chan. And there was a point in time where you couldn't speak or talk, and you only recently got them… removed… so right now, it's counted as being mute and blind." He said. Sasuke nodded and brought his hand up to his neck, where his Konoha headband was hanging. Ken also lifted his hand and put it over Sasuke's.

"Does it hurt?" he asked. Sasuke shook his head. _Not at the moment. The only place that hurts are my eyes._ He said. Ken clenched his teeth and put his fingers on Sasuke's eyelids.

"Why did it have to be you to receive all that? You didn't even do anything wrong." Ken whispered. Sasuke smiled and shook his head. _I guess that they got sick of me winning every round._ He said. Ken shook his head and sighed.

"But still. It's not fair. It's not humane to just rip them out like that while you're still conscious. You couldn't even scream!" he said. Sasuke gave a silent huff and whacked Ken's head, making him clutch his head in pain.

"What was that for, Sasu-chan?!" he asked, pouting. Sasuke just shook his head. _Stop getting all mushy on me. We made it out. That's all that matters. It's not going to happen again, right?_ He asked. Ken smiled and nodded.

"No it isn't. If they come back for you, then I'll b*tch slap their stupid sadistic a**es into the next year and be there to b*tch slap them back when they get there." He declared. Sasuke laughed silently and Ken smiled back.

"Well, be sure not to attempt talking or eating solids. Don't laugh too hard either. We don't want that opening back up, do we?" he asked. Sasuke smiled and shook his head, taking Ken's hand and leaving the room, unaware of the pair of golden eyes watching their whole conversation… well, Ken's conversation.

{Back in Pein's office}

"Zetsu, what did you find out?" Pein asked as the plant man morphed out of the ground.

"Nothing much. **It seems like the kid has gone through lots of pain though.** Yeah, that Ken guy was just worrying over him the whole time. **That was stupid.** That's mean! I thought it was sweet. **Exactly why you're an idiot.**" He said. Pein sighed.

"Anything else?" he asked. Zetsu thought for a while.

"Well, Ken was saying that it wasn't fair that Sasuke had to take all the punishment for not even doing anything. **And how he couldn't even scream in pain and something about ripping 'them' out. I have no idea what though.**" He said. Pein nodded.

"Good job, Zetsu. I will personally ask them later. Konan, prepare for a meeting." He said. Konan smiled and started the preparation for the meeting.

"MEETING! GET YOUR LAZY A**ES HERE NOW OR NO DINNER FOR THE REST OF THE YEAR!" Pein yelled. All the members sweat dropped at that. Ken sighed and led Sasuke out of the room and to the meeting room where most of the members were already in their seats. Ken and Sasuke stood in the back while Pein looked at them and gestured for them to choose an empty seat and sit. Sasuke chose the seat to the right of Itachi and Ken sat in the seat next to Sasuke.

"Everyone's here?" Pein asked. When everyone nodded, Pein started the meeting.

"This meeting is to discuss the two new members we received today. Uihara Ken and Uchiha Sasuke. We are aware that you want to keep your reasons of joining Akatsuki a secret, but we cannot allow that for you may be a spy from Konoha trying to get information out of us." He said. Ken sighed and looked at Sasuke, who was tense and nervous.

"Very well. I will tell you, but please refrain from telling others." Ken requested. Pein nodded and Ken started talking.

"Well, first of all, Konoha betrayed us. They have this place called Deadman Wonderland. It's supposed to be an amusement park, and it is, but it is also a prison. It's one of the cruelest prison's out there. They torture their prisoners to death and show no mercy. Sasuke and I were thrown in there for no reason. When we asked, they said that we were 'too dangerous' and that we 'cannot be allowed access to the outside world'." He started. Itachi stared at Sasuke, who gripped Ken's hand harder.

"There, everyone was tortured to death somehow. Either by dying in the 'games' they hold, or fighting to the death in the tournaments. We were two of the people who were made to fight to the death. Sasuke was put up against me, and since we both got to know each other so well, we both didn't want to fight to the death. Sasuke gave up, saying that he couldn't fight, and he was forced to do the 'punishment game' as they call it. It was so cruel. They ripped out his vocal cords so he couldn't scream or speak, and then ripped out his left eye. And all this was done while he was conscious!" Ken clenched his fists in anger.

"They said that I had to go through the punishment game too, but Sasuke stepped in and punched one of them, making them give my punishment to him. My punishment was going to be my right eye, so they ripped out his. They punished him for doing absolutely nothing. They threw us in that h*ll for absolutely no reason, but it kind of makes sense that they would do that considering that Danzo's the one who ordered it." He said. Itachi stiffened slightly at the mention of Danzo, but nobody except Sasuke, Ken, Kisame, and Pein noticed. Pein nodded.

"Go on." He said gently[?]. Ken took in a shaky breath and Sasuke squeezed his hand for reassurance.

"Well. That's about it. We only recently escaped that wretched place along with some others that we had managed to free after destroying the place. Sasu-chan is actually very strong, even if he doesn't look like it. He blew up the whole amusement park along with the directors of that place. Words couldn't describe how happy I was when I saw that. The people who tortured us, experimented on us, and killed us were dead. Deadman Wonderland was gone. All of us held a mini celebration after that, but Sasu-chan, he couldn't enjoy it. He couldn't see and couldn't speak, and most of all, he was in severe pain. It was just two days ago that it happened. All the prisoners went back to their villages and we came here." Ken finished, looking at Sasuke, who was holding his hand a bit too hard for his comfort. Sasuke seemed to sense his discomfort and loosened his hold a bit. Pein thought over the story and nodded to Konan.

"Konan, prepare two cloaks for them. You two, Uihara Ken and Uchiha Sasuke, will be official members of Akatsuki. Sasuke, have Sasori look at your wounds. Once you have healed, you two will be tested to see if you are fit to be members. Yes, I said that you will be official members, but we still need to test your strength. Ken, you will be against Itachi. Sasuke, you will be against Kisame. Sasori, take a look at Sasuke and heal him as best as you can. Dismissed." He ordered. Sasori looked at Sasuke.

"Come with me." He said in his gruff Hiruko voice. Sasuke stood up and pulled Ken with him. _Can you come with me?_ He asked. Ken shrugged and looked at Sasori.

"Sasori-san, can I come with?" he asked. Sasori looked and nodded.

"Hurry up. I don't like to be kept waiting." He said and started walking to his room with Ken and Sasuke following close behind. Once they got to Sasori's room, he got out of Hiruko, revealing himself to be a very good-looking redhead. Ken stared at him.

"Oh… so you're Akasuna no Sasori." He said. Sasori nodded and motioned for Sasuke to sit on the bed.

"I need to check your wounds first. Take off your hitai-ate." He said. Sasuke tensed and clutched his hitai-ate, not wanting to take it off. Ken knelt down in front of him and gently rubbed his hand.

"Sasu-chan, take it off for a minute? Sasori-san has to see so he can heal you. Please?" he asked. Sasuke hesitated, but took his hand away, allowing Ken to take off his hitai-ate. Sasori looked at Sasuke's neck and his eyes widened.

"What did they use?" he demanded answers. Ken looked worried.

"They used a butter knife and tweezers." He answered. Sasori sighed.

"I'm afraid that I cannot heal that. His vocal cords were removed wrongly and to heal it properly, I would have to get new vocal cords and perform surgery that may cost his life. I'm guessing that it was the same for his eyes." He said. Ken shook his head.

"No, for his eyes, they used something similar to one of those salad fork things. You know the things that look like scissors but for tossing salad?" he asked. Sasori nodded.

"I see. I'm sorry to say that I cannot heal these wounds. I can take away the pain though." He offered. Ken nodded.

"Please do. Sasu-chan, it'll be okay. You'll be just fine. He won't do anything bad to you." He said when Sasuke started shaking. _I'm scared. I'm scared, Ken-nii. W-what if they don't grow back?_ He asked. Ken sighed.

"Sasu-chan, they will. You'll be able to do both again. I promise." He said. Sasuke calmed down a bit then and Sasori gave Sasuke a pain killing shot.

"What can't he do?" he asked. Ken thought over the long list of things Sasuke couldn't do.

"He can't eat hard stuff, he can't have solids in large amounts, he can't talk, he can't see, he can't stay awake for long periods of time, and there's lots more that I will not say at the moment. I'll give you a written list." He said. Sasori nodded.

"What did you mean by not being able to stay awake for long periods of time?" he asked. Ken sighed.

"Well… it's been like this for a while now, but he can't stay awake. He'll be awake for two days, and then fall asleep for five years. That's kind of why I kind of spoil him. He's only awake for so little time and unconscious the rest." He said. Sasori nodded.

"I can't completely get rid of it, but I can decrease the time he's asleep and increase the time he's awake a bit. Like he'll be awake for a week and asleep for around a year or less. Something like that." He said. Ken's eyes widened.

"You can? Please do it!" he said. Sasori nodded and did some hand signs.

"Go nenkan kinjutsu: Toki o nobasu!" he said and touched Sasuke's forehead. Sasuke fell limp in Ken's arms and Sasori sighed.

"My work is done. He'll wake up in a few hours." He said. Ken nodded and bowed to Sasori.

"Arigato gozaimasu!" he said. Sasori just waved his hand.

"It's fine. Now go find Itachi and bug him or something." He said. Ken nodded and smiled, picking up Sasuke and went to find Itachi.

"Itachi-san, Itachi-san, where are you?" he asked.

"Here." Itachi said, looking up from the scroll he was reading from the couch. Ken smiled and sat on the couch next to him, Sasuke still asleep in his arms. Itachi saw and gave Ken a questioning glance.

"Oh, Sasori-san helped. Now Sasu-chan won't be in so much pain anymore." He said smiling. Itachi nodded and stood up, looking at Ken.

"Follow me." He said and walked towards his room. Ken smiled and followed. When they were in Itachi's room, Itachi did some hand signs and sound-proofed the room.

"Uihara-san, what is the relationship between you and my brother?" he asked. Ken smiled.

"He's like a little brother to me. He even calls me Ken-nii!" he quietly squealed. Itachi nodded.

"How did you first meet?" he asked. Ken's happy smile turned bitter.

"He saved me. I told you guys didn't I? We met in Deadman Wonderland. I was about to be killed by a droid they sent and he saved me. He kicked the robot out of the way and blew it up. We became friends after that. On the outside, he seemed like he was a heartless bastard, but once you get to know him, he's just a little boy who misses his brother." He said. Itachi's eyes softened and he looked down at Sasuke's unconscious form. Reaching out, he gently brushed aside a few locks of hair that had fallen onto his face.

"I'm sorry, Sasuke. I never should have left you." He softly said. Ken smiled at the exchange and gently tried to shake Sasuke awake, but it didn't work. Ken sighed.

"I don' wanna wait a few hours for Sasu-chan to wake up…" he whined softly. Itachi smirked and shook his head.

"What else happened while you were 'there'? Are there any good memories?" he asked. Ken smiled and nodded.

"Of course there are. After they did this to Sasu-chan, our little group of friends went on a rampage and killed mostly all the directors except for the maker of the 'games' and 'tournament'. We killed him slowly and painfully, using all the stuff he did on us. We made sure that he died in pain. That has got to be the best memory I've had. We stopped them from doing more wrong. We also got our revenge for what they did to us. Even though they didn't do much to me, they did so much to my Sasu-chan. He was always the one who received the brunt of the attacks they made on us. He was the one who always ended up unconscious for weeks trying to recover from life threatening injuries. We all couldn't take it anymore, so we planned a coup d'état. Everyone got their weapons ready, and in our case, our blood." Ken said and laughed when he saw Itachi's look when he said blood.

"You see, there's a section for people who can use their own blood as a weapon. We're the people who can use Tsumi no Eda, the branch of sin. We're confined to the G-sector and we're the ones used in the Corpse carnival, in other words, the fight to the death. To them, we were their toys to play with and break in the cruelest most painful ways possible." Ken sighed.

"Sasu-chan is the only Tsumi no Eda user that can freely control blood. It doesn't matter whose blood it is. He can control them all. He also has some awesome ninja skills. I forced him to show me one of those jutsu things you guys use and it was awesome! It was just a huge fireball shooting from his mouth. I kinda freaked out and took him to the medical ward to get his mouth checked after I saw that." Ken sheepishly rubbed the back of his head. Their conversation continued for a few hours and Sasuke finally started to wake up. He slowly sat up and cutely yawned, making Ken 'aww' at his suppsosed cuteness. Itachi reached over and pulled Sasuke into a hug, making him go ridged in his grasp. Ken smiled and patted Sasuke's head.

"It's fine, Sasu-chan. It's your brother." He said and Sasuke calmed down, his body becoming less tense and gently hugged back. _I missed you, nii-san._ He said. Itachi was surprised to hear Sasuke's voice in his head, but smiled and hugged a bit tighter.

"I missed you too, otōto. I'm sorry for leaving you. I'm so sorry for making you suffer." He said. Sasuke nodded and hugged Itachi tighter. _I missed you. You just left after killing everyone. Why did you do it nii-san? It wasn't like you to do that. That wasn't you!_ He said. Itachi sighed.

"Otōto, if I didn't do it, then Konoha would've burned to the ground. But now that I heard what they did, I regret killing the clan. But I also don't. You deserved so much more than you got from them." He said. Sasuke smiled and nuzzled Itachi's cheek with his own, making Itachi chuckle.

"Sasuke, can you open your eyes? Please, I don't care if they're empty." He said. Sasuke hesitated but nodded, slowly opening his eyes. Itachi gasped at what he saw. Sasuke's eyes were empty sockets, but there was a mini eyeball in each socket.

"Sasuke, I think your eyes are growing back…" Itachi said, both happy and creeped out at the same time. Sasuke brightened up after hearing that and jumped on Itachi, knocking them both to the ground. _Arigato nii-san! They're growing back… they're finally growing back!_ He said happily. Itachi looked confused.

"How do you know this? Has it happened before?" he asked. Sasuke stopped his mini-celebration and nodded. _Hai. Twenty times before. They kept on saying that they'll break every bone in my body, but instead, took out my eyes. I swear that they don't know what bones are._ Sasuke huffed silently, making Itachi chuckle at his childish behavior.

"Well, I hate to break this to you, but it's getting late. We both have to fight tomorrow, so goodnight?" Ken asked. Itachi nodded and hugged his brother again. Sasuke smiled and kissed Itachi on the cheek, grabbing Ken's hand. _Ken-nii, can I stay with nii-san tonight? I mean, we just found each other again…_ he asked, cheeks tinged pink. Ken laughed and nodded, patting Sasuke on the head.

"Go ahead, Sasu-chan. Ask him though." He said. Sasuke nodded and grabbed Itachi's hand again. _Nii-san, can I stay with you tonight?_ He asked. Itachi smiled and nodded.

"Of course. If it makes you feel better, Uihara-san's room is linked to mine by that door." He said, gesturing to a door that Ken thought was a closet.

"So that wasn't a closet…" Ken mused and shook his head,looking at Itachi. "Oh, and Itachi-san, please don't call me Uihara-san. Ken will do just fine. I swear that my parents hated me… they named me after a friggin' Barbie doll!" he exclaimed, throwing his arms in the air in exasperation and storming into his room. Once he was out, Sasuke started laughing silently, soon joined by Itachi's chuckling as he released the jutsu.

"Goodnight, Sasuke. I promise that we'll be together from now on." He said, kissing Sasuke's forehead. _Hai, nii-san. I love you. Goodnight._ He said. Itachi smiled one last time before falling asleep with his brother in his arms.

Chapter 1 is done. So… Like I said in the disclaimer, I used Deadman wonderland in this one. You like?


	2. Chapter 2

Blood of the innocent chaper 2

Disclaimer: I do not own Naruto or the other anime's I may be using. I only own my OC's. If you don't like my crappy writing, then by all means, don't read it.

Sunlight poured into the room, brightening it almost instantly and waking up a certain Uchiha (Weasel). Itachi woke up and saw that he was no longer sleeping with Sasuke by his side. He sighed and shook his head. 'I should've known. That was too good to be true.' He thought, but when he went downstairs to the kitchen, he was surprised at what he saw. Sasuke was standing in front of the stove making pancakes with Ken beside him, talking softly.

"Sasu-chan, you know he'll be happy. Just do it for him?" he asked. Sasuke blushed slightly and shook his head, flipping a pancake onto the large stack on a plate. Ken pouted.

"But Sasu-chan! You're almost healed all the way, but you'll still not be able to see or talk unless it's an emergency! Please? You know you want to." He said. Sasuke gave an inaudible sigh and nodded his head. _Fine, Ken-nii. But just this once though._ He said. Ken beamed and hugged him after he flipped the last pancake onto the plate and brought it to the breakfast table.

"Otōto, what's wrong?" Itachi asked, seeing Sasuke's blush. Sasuke jumped a little and his blush deepened, but he shook his head and buried his face in a pillow he magically pulled out. Itachi chuckled at his shyness and patted his head.

"It's alright, otōto. You don't have to tell me. But please tell me this one thing. You were put on Team 7 with Kakashi, weren't you?" he asked. Sasuke nodded and Itachi sighed.

"Well. It seems that he broke his promise to Obito then. He said that he would protect his students and comrades, but it seems like he let you go." He said. Sasuke shrugged and held Itachi's hand. _It's not like it matters, does it? At least I get to be with you and Ken-nii._ He said. Itachi nodded.

"Ne Sasuke, why do you call Ken-san 'Ken-nii'?" he asked. Sasuke shrugged again. _Well, when we were still 'there', he was about to get killed by a robot droid thing, so I kicked it and it blew up. He keeps on saying that I saved him and that he'll protect me with his life and give me anything I want that's within his power. It was around the time where you left, so I requested that he be my surrogate brother. He was more than willing. I've tried telling him a few times that he doesn't have to if he doesn't want to, but he just says, 'It's my duty to protect you. I swore it to the graves of our deceased comrades that I would. I know that I can't fill the space that your brother has made, but I will try my best.' He won't stop saying that and sometimes it gets annoying. He doesn't have to do this, but he feels like he has to._ He said. Itachi nodded and walked over to Ken, sitting down next to him and Sasuke sitting next to Itachi.

"Ken-san, why did you become Sasuke's brother?" he asked. Ken looked at Itachi and smiled.

"Well, Sasu-chan _did_ save me after all. I feel like it's the least I can do to make up for what I made him lose. I know that I can't heal his emotional wounds, but I can at least dull the pain." He said. Itachi sighed.

"So you feel as if it is your duty to protect my otōto because he saved you." He said. Ken nodded.

"Partially true, but I also want to become his surrogate brother. I know that Sasuke wouldn't want me to though. He already has you, so he might not want me to become his brother too." He said sadly. Itachi nodded.

"I understand your thinking, but have you ever thought of what Sasuke would feel if you didn't fully want to become his brother? He thinks that you're only doing this because he asked you. He feels like he's forcing you into doing something you don't want to do." He said. Ken shook his head with wide eyes.

"That's not it! I really want to, but I also feel like I have to." He said. Itachi sighed and turned to Sasuke, who was sitting next to him.

"You heard him, Sasuke. What do you want?" he asked. Ken's eyes widened as he noticed Sasuke sitting next to Itachi. _I want Ken-nii to stay being Ken-nii. Nii-san is my real nii-san, but having more family can't hurt, can it?_ Sasuke said. Itachi smiled and squeezed his hand.

"It's okay, Sasuke. Having more family is definitely a good thing. Ken-san, Sasuke accepts you as his official surrogate brother. You're now a part of the family, I guess." He said. Ken smiled and waited for the other members to wake up and come down. Soon, all the other members were at the breakfast table, including Pein. They all took a look at the overly large stack of pancakes and almost tripped on air.

"Who made these?" Konan politely asked. Ken pointed to Sasuke and Itachi placed his hand on his brother's head. Sasuke blushed and buried his face into Itachi's chest, making him chuckle and surprise the crap out of the other members.

"Holy sh*t. The Uchiha f*cking has feelings…" Hidan said, Deidara nodding in agreement. Pein just sighed and sat down, followed by the others.

"Well… Thank you for the breakfast then, squirt." Kisame said with a grin. Sasuke nodded and hugged Itachi tighter. _You can eat now, you know?_ He said. Itachi chuckled again and pulled a few pancakes onto his plate.

"Itadekimasu." They said and started eating. Hidan's eyes widened as he finished his first pancake quickly.

"Holy sh*t, this is good. What the h*ll did you put into this little f*cker?" he asked. Sasuke fidgeted under their stares and froze when Ken placed a spoon to his lips.

"Come on, Sasu-chan. Open up. You know you can't eat solids yet." He said. Konan looked at Sasuke worriedly.

"Why can't he eat solids? Is there something wrong with him?" she asked, fussing over him like he was her own child. It was Sasori who answered her.

"His vocal cords have been brutally removed with a _butter knife_ and _tweezers_. He cannot eat solids in fear that his throat would be torn open and die. It also seems that he did not get proper stitches after the removal of his vocal cords, creating more risk of death if he eats solids." He said. Konan and Itachi looked at Sasuke with worry showing in their eyes while Sasuke kept on resisting the spoonful of broth that Ken had made for him. Itachi took the bowl from Ken and placed a spoonful in front of Sasuke's mouth.

"Sasuke, you have to eat. You can't eat solids and you can't survive on no food at all, so please?" he asked. Sasuke nodded and reached up to take the spoon, but Itachi pulled it away before he could take it.

"We don't want you to accidentally shove the spoon down your throat, do we?" he asked. Sasuke blushed and looked down, not liking the idea of being fed in front of everyone else. Pein sighed.

"Sasuke, we won't judge you because of your injuries. Just eat. I will punish anyone who makes fun of you." He said. This seemed to calm Sasuke down a bit and he opened his mouth just wide enough for Itachi to gently stuff the spoon in and swallowed. Itachi smiled as he saw Sasuke swallow and placed another spoonful of the broth in his mouth. Sasuke swallowed, but then suddenly covered his mouth in a silent gag and ran out of the kitchen and into the bathroom, locking the door behind him. Itachi and Ken looked on with worried eyes, wondering what happened while Konan went to the bathroom and knocked.

"Sasuke? Sasuke, come out. What happened?" she asked, but stopped as she heard the sound of regurgitating. She went back to the worried brothers and sighed.

"He's throwing up." She said. Zetsu looked at her.

"It doesn't seem that way though. **We smell blood. If we knew better, we would say that he has hematemesis.**" He said. Ken's eyes widened and he ran to the bathroom, banging his fists on the door.

"Sasu-chan! Sasu-chan, open up! Don't do this again, please!" he begged. Itachi ran up to him as well.

"Ken-san, what's wrong?" he asked, worried about his baby brother. Ken sighed and stopped banging on the door.

"Sasu-chan is sick. He has a type of Acute Leukemia, which is a cancer. Most cancer's have no cure and this is one of the cancers that have a low survival rate. Sasu-chan has had this for a while now, so his survival rate is even lower than the usual child's survival rate, which is fifty to eighty percent. His is about thirty." He said. Itachi's eyes widened.

"Is there any way to cure it?" he asked. Ken sighed again and shook his head.

"Not that I know of." He said. Sasori walked up to them.

"What kind of Acute leukemia does he have?" he asked. Ken thought for a while.

"He has Acute Promyelocytic Leukemia." He said. Sasori looked confused.

"I've never heard of it before. I've never heard of Acute Leukemia either…" he said. Ken sighed and shook his head.

"Not really surprising, really. Our friends Alice, Aoi, and Skye diagnosed him. Those three are from a different dimension. It's a disease from their world." He said. Sasori ah-ed and nodded.

"That clears things up now. Would you mind telling me about them? I would like to make a cure to those and add them to my list." He said. Ken nodded and took out a scroll.

"All the diseases that she told me about are in here along with the symptoms and stuff." He said. Sasori nodded and pocketed the scroll.

"Arigato." He said. Ken nodded and started knocking on the door again.

"Sasu-chan, I know that you hate it when people worry about you, but you have to let us help. You're losing too much blood, Sasu-chan. You'll die if this continues!" he yelled. There was an almost inaudible sigh and the door opened, revealing a blood covered Sasuke. Itachi's eyes widened when he saw all the blood and pulled Sasuke into a hug, ignoring the blood that got on his cloak.

"Sasuke, please let us help. We'll do what we can to help you." He said. Sasuke nodded and hugged back, but pulled back and ran back into the bathroom and leaning over the toilet. Itachi walked into the bathroom and patted Sasuke's back and held his hand as he threw up, but his eyes widened as he saw the sticky red substance his brother was spitting out.

"S-Sasuke… what happened?" he asked. Sasuke shook his head, Itachi still holding his hand. _It's nothing much._ He said. Itachi gave him a glare.

"Nothing much? If it was nothing much, then you wouldn't be barfing up blood!" he said. Sasuke shook his head again. _It's kinda normal in Acute Promyelocytic Leukemia. You kind of get used to it after having it for ten years._ He said. Itachi's eyes widened.

"You've had it since you were three? How come I never noticed?" he asked. Sasuke coughed and threw up some more. _Y-you *cough* were never around much. *cough* You were almost always away on missions or training._ He said. Itachi looked down at his brother guiltily.

"I'm so sorry, Sasuke." He said. Sasuke shook his head and sighed as he finally finished his little blood coughing session. _It's not your fault, nii-san. You were too busy to notice._ He said. Itachi shook his head, completely forgetting about the rest of the Akatsuki watching them with wide eyes.

"That's no reason for me to ignore you all the time. I'm sorry Sasuke. I should've paid more attention to you. Then you might not have this disease." He said. Sasuke smiled and wiped his mouth, smearing the blood onto his hand and around his face. _It's still not your fault. To tell the truth, when Shi-nii took me to the hospital to get it checked, they said that I was born with it and it couldn't be cured. And that I would die at age ten. But I'm still alive… they might have done a wrong diagnosis._ He said. Itachi stared at his brother, guilt clearly showing in his eyes. Sasuke sighed again. _Nii-san, stop worrying and get back to doing what you usually do. You don't have to worry about this. I'm pretty sure that it'll go away and stop feeling so dang guilty._ He said. Itachi sighed and nodded, hugging Sasuke again.

"Fine. I'm sorry for not being there." He said. Sasuke smiled and hugged Itachi again. Ken sighed.

"How nice of you to forget that we were here." He mumbled. Sasuke and Itachi pulled apart from their hug to face a very surprised Akatsuki and a semi pissed Ken. Itachi sweat dropped and pulled his brother and himself up to their feet.

"Well then…" he started. Pein stepped forward.

"Sasuke, what is it with this cancer you have? It's so bad that it causes you to literally throw up blood and you only have a thirty percent survival rate?" he asked. Sasuke looked at Ken, who sighed.

"Pein-sama, let me say it this way. Leukemia is a cancer that attacks the bone marrow and blood cells. Acute Promyelocytic Leukemia is just a form of Leukemia. It's just that since he's had it for so long, the effects of the cancer are getting stronger. There's no treatment for cancer here and I'm surprised he's not bald yet…" he said. Sasuke glared at Ken and whacked him over the head. _I'm not going to be bald…_ he muttered, making Ken snort and Itachi chuckle. Sasuke blushed and pouted cutely, making Itachi and Ken hug him.

"You're not going to go bald, Sasu-chan! Even if you do, I'll still love you!" Ken cooed. Itachi nodded. Sasuke blushed again and hid his face behind his hands. Pein let a small smile pass as he looked at the three.

"Well… how do you lessen the effects of this cancer?" he asked. Ken looked over to him, pausing in his hug Sasuke attack.

"I'm not really sure. I think it was that he needs a lot of vitamin A and or ATRA. And then chemotherapy." He said. Pein nodded.

"Sasuke, Ken. Your tests will be postponed until three days later." He said. Ken smiled and nodded.

"Arigato, Pein-sama. Sasu-chan, do you think that you would have healed by that time?" he asked. Sasuke nodded and Itachi smiled.

"I'm happy, otōto. You'll finally be able to see and speak." He said. Sasuke looked guilty and shook his head. _No… I still can't. I'm not allowed to open my eyes and or speak unless in a life or death situation._ He said. Itachi looked confused.

"Why?" he asked. Ken sighed.

"Well, you see… Sasu-chan is very very very _very_ strong. He has so much power that his body can't contain all of it, so it somehow sent most of it to his eyes and voice, so if he opens his eyes and or speaks, everyone around him within a fifty mile radius will die from the pressure. And if Sasu-chan says 'die' to someone, then that person will automatically die. That's why he can't. He can speak really softly without killing anyone though. He can also see if he wears special sunglasses. I have a couple pair with me that were made for him." He said. Itachi nodded and hugged his brother.

"You've gone through so much." He whispered. Sasuke smiled. _Not really. If you look at it, I've only gone through like ten bad things. You've gone through, what, five hundred?_ He said. Itachi scoffed.

"Not that much, otōto. The worst I've gone through is killing the clan and joining the Akatsuki. I only have to carry around the burden of the clan and the hunter nin's while you've gone through getting your vocal cords and both eyes brutally ripped out while you were conscious, getting tortured on a daily basis, having that cancer, and now that you're here, you'll have to deal with the hunter nins and other ninja's hunting us too." He said. Sasuke shrugged. _Oh well… doesn't really matter as long as we're together, does it?_ He said. Itachi smiled and nodded.

"Ah. Everything's going to be okay." He said. Ken smiled and nodded.

"True dat… crap. I sounded like Skye-chan just now. CRAP! HER HABITS ARE RUBBING OFF ON ME!" he screamed while holding his head. Sasuke burst out laughing… well, as best as he can with no vocal cords. Itachi chuckled and the rest of the Akatsuki snickered at Ken's actions.

"D*mn… **he's like Tobi.**" Zetsu said. Deidara nodded.

"True, un. I'm so glad that Pein-sama sent him on a long mission, hmm." He said. Ken heard their conversation and glared at them.

"You guys are so mean…" he pouted. Deidara gave him a look.

"We're the bad guys, yeah. We're supposed to be mean, un." He said. Ken kept his pout and hugged Sasuke, who silently sighed.

"Sasu-chan… they're so mean." Ken said. Sasuke shook his head. _Ken-nii, they're the Akatsuki, a criminal organization filled with S-ranked criminals. They're supposed to be mean. If they weren't, then who would take them seriously?_ He said. Itachi gave a small smile.

"Otōto, you know a lot." He said. Sasuke smiled. _Not really. Just some stuff here and there. I'm not a walking Wikipedia like Kōri-chan is._ He said. Itachi looked confused.

"Kōri-chan? Who's that?" he asked. Ken looked at him.

"You know, one of the three girls who gave Sasu-chan his diagnosis. Skye, Aoi, and Alice? Kōri-chan is Alice's nickname." He explained. Itachi nodded and looked back down at his brother.

"Sasuke, did you take the Chuunin exams yet?" he asked. Sasuke shook his head. _No. Kakashi-sensei said that we weren't ready yet and that we have to wait until the next exams. Also, the time for entering the Chuunin exams hasn't come yet._ He said. Itachi nodded.

"How would you like to be entered?" he asked. Sasuke shook his head. _Not happening. So not going back there._ He said. Itachi looked at his brother sadly.

"Sasuke, what _did_ they do to you there? For you to not want to go back to the place you once called home." He asked. Sasuke shrugged. _Nothing anyone really needs to know about right now…_ he said. Itachi shook his head.

"No, otōto, I need to know. I know that I haven't really been a good big brother, but I am still your brother. Please tell me, otōto." He said. Sasuke sighed again. _Well… it looks like everyone else wants to know too…_ he said. Itachi looked at the rest of the Akatsuki, seeing their curious looks.

"Would it make you feel better if they weren't listening?" Itachi asked. Sasuke shook his head. _No, it's fine. Just let Ken-nii tell you guys. He knows everything they did too. That way, everyone can hear what happened if they want to._ He said. Itachi nodded and turned to Ken.

"Ken-san, Sasuke said that he would feel better if you told us." He said. Ken sighed and nodded.

"Fine, but no interruptions or I won't tell you guys anything anymore." He said. Pein nodded.

"We will not interrupt you." He assured. Ken nodded and started.

"Well… where to start." He wondered.

"How about from the beginning?" Kisame asked. Ken nodded.

"Okay then. Well, first, it was just a normal day. Sasu-chan was with his team and they were just getting to know each other. It was the day that the team first met, so they were doing the introductions…"

{Don't feel like writing him talking so much, so see for yourselves what happened.}

"Well… since we've just met, let's do some introductions." Kakashi said with an eye smile. Sakura looked confused.

"What do you mean?" she asked. Kakashi looked at her.

"Hmmm… your likes, dislikes, hobbies, dreams for the future, and stuff like that." He replied. Sakura nodded.

"How about you go first, Sensei? We hardly know you." She suggested. Kakashi put on a thinking face.

"Hmmm… me, huh? Well, I'm Hatake Kakashi. I have lots of likes and not so many dislikes. I have many hobbies and my dream for the future… I'm not telling you." He finished with an eye smile.

"All we learned was his name…" Sakura whispered to Naruto, who nodded. Kakashi looked at the three genin before him and pointed to Naruto.

"Alright, blondie. You first." He said. Naruto glared at being called blondie, but grinned seconds later.

"I'm Uzumaki Naruto! My likes are ramen, being a ninja, Hokage no jii-chan, when people recognize me, and my friends! My dislikes are the three minutes I have to wait when making ramen, when people look down on me, bullying, and people yelling at me. My hobbies are training and eating ramen. My dream is to become Hokage one day so nobody will look down on my ever again!" he said with a proud grin. Kakashi stared at him. 'He's grown up differently…' he thought and looked to Sakura.

"Alright, you next, pinky." He said. Sakura nodded.

"Well, I'm Haruno Sakura. I like… [Looks to Sasuke and squeals]. My hobbies are… [Looks to Sasuke and squeals… again] My dreams are… [Looks at Sasuke and squeals again and again…] and I hate Naruto!" she shouted, pointing to the blonde, who looked heartbroken. Kakashi sighed. 'It seems that girls now only care about love…' he thought and then turned to Sasuke.

"And finally, the brooding boy here." He said. Sasuke looked up at Kakashi and frowned.

"I'm Uchiha Sasuke. I like some things and I don't really have any dislikes. My hobbies are none of your business and as for my dream… it's more of a goal though. I will find and kill a certain man." He said. 'Danzo must die!' he thought. Kakashi looked at him with his eye filled with sadness, though he didn't show it. 'So he's really after his brother. I knew he would be differet, but to think he changed this much…' he thought. Kakashi stood up and smiled his famous eye smile.

"Well, you're all unique in your own way. Team 7 will have their first mission tomorrow." He said. Naruto jumped up excitedly.

"What is it?!" he asked. Kakashi smiled.

"A survival mission." He said. Sakura looked confused.

"Survival mission?" she repeated. Kakashi nodded.

"Yup." He said and started chuckling darkly. Naruto looked at him weirdly.

"What's so funny, Kakashi-sensei?" he asked. Kakashi grinned.

"If I told you, then you would chicken out." He said. Sasuke held in a small laugh and tilted his head to the side cutely, making Sakura squeal.

"Really? What is it?" he asked. Kakashi chuckled darkly again.

"Do you really want to know?" he asked. The genin nodded their heads.

"This survival test is to see who is ready for genin. It's like a test again. There's a sixty three percent failure rate and so far, nobody has passed my test yet." He said. Naruto and Sakura started freaking out while Sasuke just stared at Kakashi like he grew another head. Kakashi noticed his stare and gave him a confused look.

"What it is it?" he asked. Sasuke looked at Kakashi's hair.

"Your hair defies gravity…" he said, and then pointed to his own hair. "Kind of like mine…" Kakashi sweat dropped.

"Well… it seems like you two are already chickening out. Well, come here tomorrow at seven prepared. Oh, and don't eat breakfast. You'll puke." He said with an eye smile and poofed away. Sasuke shrugged and started walking out back to his apartment when Sakura followed him.

"Ne, Sasuke-kun, ummm… do you think that we can go out sometime? To get to know each other better?" she aske with a blush. Sasuke shook his head.

"No." he said and ran away, leaving a disheartened Sakura. When Sasuke got back to his apartment, he was surprised to see three ANBU standing in front of his door waiting for him.

"Uchiha Sasuke?" the bear masked ANBU asked. Sasuke nodded and the monkey masked ANBU grabbed his arm.

"We are under the orders of Danzo to bring you to him. Do not resist." He said. Sasuke looked confused, but nodded.

"What do you need?" he asked.

"We don't know, but it is of importance." Bear answered. Sasuke nodded and the ANBU poofed away with him. When they got to Danzo, the ANBU bowed and poofed back away.

"Well… Sasuke-kun. I'm sure that you're confused about why you're here." He said. Sasuke nodded.

"You see, I have this program going on. It's called Deadman Wonderland. We gather contestants and send them there to compete in the games. It's very entertaining and fun. What do you say?" he asked. Sasuke shook his head.

"I don't think so. I can't just leave Team 7." He said. Danzo smiled.

"Actually, you can. You yourself will be leaving, but we'll send in a replacement. A clone to be exact. It has your abilities, your look, and your voice, so it will be like you never left to them." He said. Sasuke still shook his head.

"No, I still have to find _him_. I won't join until he is dead." He said. Danzo sighed.

"Well, I tried being nice, but it seems like I have no choice, do I?" he asked. Sasuke looked confused as Danzo called in the ANBU from earlier.

"Take him to Deadman Wonderland." He ordered and the two ANBU took Sasuke after knocking him out.

{At Deadman Wonderland}

Sasuke woke up and looked around the room, seeing someone sitting beside his bed.

"A-ano… where is this?" he asked. The man turned around and looked at Sasuke with his brown eyes.

"You're at Deadman Wonderland. In other words, H*ll." He said. "Were you taken by Danzo too?" he asked. Sasuke nodded and the man sighed.

"He's taking children now, huh? I'm Uihara Ken. What's your name?" he asked.

"Uchiha Sasuke." Sasuke replied. Ken frowned.

"You're not really talkative, are you?" he asked. When Sasuke didn't answer, Ken sighed and started walking out the door.

"Well? You coming?" he asked. Sasuke quickly got out of the bed and walked out with Ken. Out of the room, Sasuke saw lots of people with a white collar around their necks.

"Ken-san, what's with those?" Sasuke asked, pointing to a collar. Ken sighed.

"Well… those are the things that 'keep us in place'. You, Shiro, and I are the only ones who don't have it." He said. Sasuke looked confused.

"What do you mean?" he asked.

"It basically means that if we step out of line, these collars will kill us." A boy next to Sasuke said.

"I'm Ganta, what's your name?" he asked. Sasuke looked down.

"Sasuke." He said. Ganta nodded and smiled.

"So I heard that you wanted revenge on a man. Who is it?" he asked. Sasuke leaned in and cupped a hand around Ganta's ear.

"Danzo." He whispered. Ganta's eyes widened and he smiled.

"Really?" he asked hopefully. Sasuke nodded and Ken smiled too.

"Well… we kinda have to go now. Good luck, Ganta." He said. Ganta smiled back and went back to his room. On the way back to their room, Ken and Sasuke were attacked by a droid, but Sasuke's super ninja skills kicked in and he kicked the droid into pieces, greatly surprising Ken.

{Five days later: Carnival Corpse}

"Welcome! Today in the Carnival Corpse that you've all been waiting for, there is a surprise for everyone! We have gotten a newcomer recently. He will be the first Deadman to receive a name that's not a bird!" the announcer said, getting cheers and gasps from the audience.

"Sa! He will be the second Wretched Egg!" the announcer shouted, earning gasps from the audience. A moment of silence… then cheers. The announcer grinned and gestured towards the door.

"Now, welcome Vulture and the second Wretched Egg!" he shouted. The crowd cheered as smoke filled the battleground. Once it cleared, it revealed Sasuke and Ken standing on opposite sides, Sasuke staring at Ken with sad eyes.

"Ken-san…" he whispered. Ken looked at Sasuke with eyes filled with remorse.

"I don't want to do this…" he whispered. Sasuke looked down and raised his hand.

"I… I don't want to fight. I give up." He said. Ken stared at Sasuke with wide eyes filled with fear.

"S-Sasuke! What are you doing?! You'll have to go through the punishment game!" Ken shouted. Sasuke shook his head.

"I don't care." He said. The announcer/judge sighed.

"It seems like the Wretched Egg doesn't want to fight. It's alright though, since it's his first time in Deadman Wonderland. But the rules are the rules. Now for the punishment game. Pull the lever and say stop whenever." He said, tying Sasuke to a chair. Sasuke pulled the lever and the images started spinning.

"Stop." He said. The images stopped and on the screen showed a three in a row for voicebox. The workers tightened the straps on Sasuke and the nurse came up to him, taking a butter knife from the tools cart. She placed the knife on Sasuke's throat and smiled.

"Don't worry, Wretched Egg. This won't hurt much." She said and slowly started to cut. Sasuke's eyes widened in pain and he clenched his teeth together. Slowly, the knife cut through and the nurse took out a pair of tweezers, reaching into Sasuke's throat and ripping out his voicebox. Sasuke gave a silent scream of pain, blood pouring out from his neck. The nurse smiled and turned to Ken.

"You're next. Eyes, huh?" she asked and walked to Ken, but Sasuke hit her with his shoe and angered her. She grinned evilly.

"So you want it instead?" she asked. She picked up the 'eyeball remover' and slowly and painfully pulled out Sasuke's eyes. Sasuke's silent screams giving her the pleasure she wanted. Once she was done, she unstrapped him and threw him to Ken, who caught him and cradled his body in his arms.

"Sasuke… why?" he asked. Sasuke slowly grabbed Ken's hand. _I don't want to lose someone again._ He said into Ken's mind. Ken looked surprised, but his eyes softened and he smiled, running out of the Carnival Corpse with Sasuke in his arms.

{back to reality}

The Akatsuki stared at Sasuke with wide eyes and Itachi pulled Sasuke into a tight hug.

"That was only the first time they did that?" he asked. Sasuke nodded. Konan went over and wrapped her arms around the young Uchiha.

"Sasuke, you poor boy! It must have hurt so bad. How many times did they do it?" she asked. Sasuke stared at her and took her hand. _Twenty times in a row. Once they grew back, they removed them again and again._ He said. Konan gasped and hugged Sasuke tightly.

"Sasuke, please don't hide these things from us again. Please let us help you. You're still young. We're all here to help, so don't hesitate to ask." She said. Sasuke nodded and Itachi turned back to Ken.

"So then what happened?" he asked. Ken sighed and looked up at the ceiling.

"Well, you basically know the rest now. They came and tortured him daily. Sasu-chan was in so much pain. He nearly died every day and our friends would find a way to heal him. And when he finally revealed his Tsumi no Eda, they took their torture to the next level and raped him every day. They tortured him first, then raped him when he couldn't do anything. It was horrible. He couldn't scream or see either." He said. The Akatsuki were getting pissed. How could Konoha do that to a thirteen year old boy? Sasori narrowed his eyes.

"So you're telling me that Konoha, the village that Itachi used to want to protect did this to you? How old were you when it started?" he asked. Sasuke shrugged. _About three, I guess. It was at night, so nobody was paying attention. They kept me there for ten years with a clone in my place in the Academy. Then after that, you know what happened._ He said. Itachi's eyes were wide.

"Three? But how could I have not noticed?" he asked. Sasuke shrugged_. You were always busy training and doing missions. It's not really surprising._ He said. Itachi looked down guiltily.

"I'm sorry." He whispered. "It's all my fault. If I noticed earlier, then you never would've gone through all that. Ten years in there? How long has the others been there?" he asked. Sasuke shook his head. _Not long. Danzo created Deadman Wonderland especially for me and Shiro. He took me in first. I was there for the longest._ He said. Itachi's eyes widened.

"What? Why would he create that h*ll just for you? What did you do wrong?" he asked. Sasuke shrugged. _I don't know. I just remember him saying that I will pay for what the Uchiha's did or something like that._ He said. Ken just stared at him.

"Sasu-chan… let's stop talking about this and give your eyes some sunlight." He suggested. Sasuke nodded and Itachi stood with him and Ken, taking Sasuke outside.

"Alright Sasu-chan, open your eyes." He said. Sasuke was hesitant, but opened them anyways. Ken gasped when he saw them. Sasuke's eyes weren't just empty eye sockets anymore. Ken could see a medium sized eyeball in each socket. They were foggy, signaling that they weren't ready to be of use yet.

"Sasu-chan, they're almost completely there! You'll be able to see soon!" he exclaimed. Sasuke smiled. _I'm so glad… being blind sucks. All you do is crash into walls and trees and trip over nonexistent rocks…_ he said with a pout. Itachi chuckled and Ken laughed.

"That would suck, wouldn't it?" he asked. Suddenly, Sasuke came to a stop, turning his head to Itachi.

_Nii-san, doesn't the Mangekyō sharingan cause blindness?_ He asked. Itachi nodded.

"They do." He replied. Sasuke nodded and placed his hand over his brother's eyes and took them off a minute later. Itachi blinked in surprise.

"It's easier to see now…" he said. Sasuke gave a silent laugh. _I know it's surprising, but I would like to have a brother that can see, thank you very much._ He said. Itachi smiled.

"So you wouldn't like me if I were blind?" he asked. Sasuke shook his head. _No, not that. It's just that it would be better if you could see. I don't want you to get brain damage by being blind and bumping into everything in sight. You also wouldn't be able to see the enemy on a mission and could die._ He said. Itachi nodded and hugged Sasuke.

"Arigato, otōto." He said. Sasuke smiled and hugged back while Ken just huffed.

"Family hug!" he yelled and joined in. Itachi and Sasuke smiled and they had a big group hug.

I finally finished this. I know it ended really stupidly, but I couldn't find a way to end it. If I continued, then it would've been like twenty pages and what, seven thousand words or more. So, I'm still using Deadman Wonderland. I kinda got the Carnival Corpse thing wrong the first few times, but I'm too lazy to fix that. I'm thinking about using Arcana Famiglia or Pandora Hearts next. What do you think? What anime should I use next?


	3. Chapter 3

Blood of the innocent chapter 3

Disclaimer: I do not own any of the anime's I use in this thing. Oh, and this chappie is for my imōto-chan who I think has a test soon on diseases or some type of crap. Well, I only own my OC's and my imōto-chan since I claimed her… and that's all. Hope you enjoy this chapter of knowledge.

It has been a few days since Sasuke's eyes had started growing back, and Ken and Itachi were ecstatic.

"My otōto will finally be able to see." Itachi whispered happily. Ken sighed.

"Well, he'll be able to see, but he won't be allowed to unless he wears the special sunglasses. He also has Acute Promyelocytic Leukemia, so his actions will be limited too." He said. Itachi sighed after hearing that.

"Is there any way he could see without the sunglasses on? Something that lets him see color?" he asked. Ken pondered this for a while before snapping his fingers.

"I can make him some contacts." He said. At Itachi's confused look, Ken explained.

"Contacts are like glasses that you put on your eyes. It's clear and if he has those, I can make it just for him and it'll let him see color." He said. Itachi nodded.

"Alright." He agreed. Ken smiled, and Sasori came running down into the living room with a semi-smile on his face. He held up the scroll Ken gave him.

"This thing is awesome! It's allowed me to come up with so much more remedies than I already have." He said. Ken smiled.

"I'm glad that I was able to help." He said. Sasori nodded and went back into his room.

{I'm sure that you're all curious to see what's in the scroll, so Imma show you and that'll be the end of the chappie *sigh* 203 pages worth of diseases… enjoy}

**Rare diseases**

**Ribose-5-phosphate isomerase Deficiency**

This is the rarest disease in the world with just one patient diagnosed with the condition. The symptoms of this disease was diagnosed after the affected boy was diagnosed with leukoencephalopathy. The patient had an increase in polyols arabitol, ribitol and erythritol in his SPECT profile. This disorder causes mutation in the pentose phosphate pathway enzyme.

**Acute Promyelocytic Leukemia**

Acute promyelocytic leukemia**,** commonly called APL, a malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid line of cells and an excess of immature cells called promyelocytes. APL is due to a translocation (an exchange of chromosome material) between chromosomes 15 and 17 which is symbolized t(15;17). This translocation is not a mere marker of APL. It is the cause of APL.

APL was first recognized as a distinct disease entity in 1957. It accounts for 5-10% of cases of acute myeloid leukemia (AML). The peak incidence of APL is in young adults. APL is considered a type of AML and is classified as the M3 variant of AML in the internationally accepted French-American-British (FAB) Classification.

The signs and symptoms of APL are nonspecific and include fatigue (feeling tired), minor infections, or a tendency to bleed (hemorrhagic diathesis). There is usually pancytopenia with low levels of red blood cells (anemia), low levels of the granulocytes and monocytes (types of white blood cells that fight infections), and low levels of platelets (that are needed for blood to clot normally). Patients with APL may therefore receive transfusions.

APL is consistently associated with a disorder that resembles (but is not identical to) disseminated intravascular coagulation (DIC). There is in APL a pronounced tendency to hemorrhage (bleeding). The bleeding can manifest itself as petechiae (little bleeding spots in the skin or elsewhere), small ecchymosis (bruises), epistaxis (nose bleeds), bleeding in the mouth, hematuria (blood in the urine), bleeding from venipuncture and bone marrow sites and in girls and women who are menstruating may have menometrorrhagia (excessive irregular menstrual bleeding). The hemorrhagic diathesis (bleeding condition) may precede the diagnosis of leukemia by 2-8 weeks.

The t(15;17) translocation in APL is the result of two chromosome breaks: one in chromosome 15 and the other in chromosome 17. The break in chromosome 15 disrupts the promyelocytic leukemia (PML) gene which encodes a growth suppressing transcription factor. And the break in chromosome 17 interrupts the retinoic acid receptor alpha (RARa) gene which regulates myeloid differentiation. The translocation creates a PML/RARa fusion gene. It produces a chimeric protein that arrests the maturation of myeloid cells at the promyelocytic stage. (It reduces terminal cell differentiation.) And this leads to the increased proliferation of promyelocytes.

The treatment of APL differs from that for all other forms of AML. Most APL patients are now treated with all-trans-retinoic acid (ATRA). ATRA is a form of "differentiation therapy." It activates the retinoid receptor RAR and causes the promyeloctes to differentiate (to mature) and this deters them from proliferating.

ATRA can induce a complete remission in most patients with APL by causing the APL-blasts to mature. However, ATRA cannot eliminate the leukemic clone. ATRA is therefore used in combination with chemotherapy including an anthracycline drug. Survival is better with the combination of ATRA and chemotherapy than chemotherapy alone in newly diagnosed APL, because ATRA + chemotherapy makes for a slightly higher rate of complete remissions while allowing significantly fewer relapses. Maintenance treatment with ATRA, and possibly with low-dose chemotherapy, further reduces the incidence of relapse.

The prognosis for APL depends on a number of factors including the white blood cell (WBC) count at the time of diagnosis, etc. Overall, more than 90% of patients with newly diagnosed APL today can achieve complete remission, and about 75% can be cured by the combination of ATRA and chemotherapy. In patients who relapse after remission, treatment may include arsenic trioxide.

The advent of ATRA therapy revolutionized the treatment of APL and markedly improved the prognosis (the outlook). ATRA syndrome is a serious side effect of ATRA treatment and includes fever, respiratory distress, and hypotension (abnormally low blood pressure). The ATRA syndrome can be prevented by the addition of chemotherapy and/or dexamethasone if the WBC is increasing.

In sum, APL is a form of acute myeloid leukemia caused by a specific chromosome translocation t (15;17). APL is associated with a characteristic cellular picture classified as M3 in the FAB Classification and responds favorably to treatments including retinoids, chemotherapy and, most recently, arsenicals.

**Apert Syndrome**

The Apert syndrome is a congenital disorder. It is characterized by the malformed skull, face, hands and feet. The fingers or toes are fused together and some patients also show Synechia. This is fusion of two or more nails of the digits. This is a slow progressive disease, where the joints continue to grow with age.

**Bloom Syndrome**

This is a rare autosomal recessive chromosomal disorder. The Bloom syndrome (BLM) or Bloom-Torre-Machacek syndrome is characterized by patients with short stature. They have a facial rash developing after they are exposed to sun. The rash looks like a butterfly shaped patch of red skin on the cheeks. These patients also have distinctive facial features, micrognathism of mandible, high-pitched voice, dilated blood vessels, etc. There are many more symptoms associated with this disease like diabetes, infertility in males, and a few patients suffer from mental retardation. You would be interested to learn more about a rare brain disorder called Ataxia Telangiectasia Syndrome.

**Creutzfeldt-Jakob Syndrome**

This is a very rare degenerative neurological disorder. The symptoms of this disease include dementia, memory loss, hallucinations as well as changes in personality. This is a progressive disease that causes death of nerve cells of the brain. This is an incurable and fatal disease.

**Zellweger Syndrome**

This is a rare congenital disorder, named after Hans Zellweger, who researched on this disorder. This is an autosomal recessive disorder that is caused by mutation of genes. It causes impairment of multiple organ system due to accumulation of lipids. Most patients do not survive beyond the age of one.

**Hutchinson-Guilford Progeria Syndrome**

Hutchinson-Guilford Progeria Syndrome is often referred to as progeria. This disease causes a person to age prematurely. It is generally diagnosed in children who are 18 months to two years old. Symptoms include stiff joints, dislocated hips, hair loss, aged-looking skin, strokes and heart disease. People with progeria live an average of 8 to 21 years, with heart disease being the most common cause of death. Another form of the syndrome, called Werner's syndrome, affects people in their late teen years. The average life span for people with this condition is 40 to 50 years.

**Creutzfeldt-Jakob Disease**

Creutzfeldt-Jakob disease is a fatal brain disease that often claims the victim's life within a year of onset. It affects one out of every 1,000,000 people, according to the National Institute of Neurological Disorders and Stroke. Visual disturbances, trouble with coordination, memory lapses, blindness, weakened extremities and behavior changes are the symptoms of this condition. Most people with the disease are around age 60.

**Lymphangioleiomyomatosis**

Lymphangioleiomyomatosis is a rare but fatal lung disease that affects only women, typically those ages 20 to 40. It affects fewer than one out of 1 million people. Symptoms are cough, chest pain, blood-tinged sputum and trouble breathing. Treatment for this condition is possible via a lung transplant.

**Nuclear Factor Kappa B Essential Modulator (NEMO)**

Nuclear factor kappa B essential modulator (NEMO) is a rare condition that affects only males. This immune-system disease is so rare that it wasn't discovered until 2007. As of August 2009, only 60 children have been definitively diagnosed with the condition. Symptoms include repeated infections, delayed tooth development with teeth that are conical when they come in, fine hair, compromised skin, ocular troubles and abnormal bone growth. The only treatment for this condition is a bone-marrow transplant.

**Menkes Disease**

Menkes disease is a condition that affects copper metabolism. It is caused by a defective gene. A child with Menkes disease usually has normal development for the first six to eight weeks of life; however, after that point, symptoms such as a low body temperature and weak muscle tone become apparent. Additionally, the infant may have seizures and colorless, kinky hair that breaks easily. Treatment for the condition is copper supplementation. This treatment won't prolong life unless it is started shortly after birth, which is highly unlikely as there isn't any screening done at birth for the condition. Without early treatment, the child will pass away by his 10th birthday.

**Neuronal Ceroid Lipofuscinoses (NCL)**

Neuronal ceroid lipofuscinoses (NCL) is the name of a group of four rare conditions: Batten's disease, Santavuori-Haltia disease, Jansky-Bielschowsky disease and Kufs disease. Collectively, these conditions are present in two to four out of every 100,000 live births in the United States. All of these except Kufs disease are fatal. Batten's disease affects children aged 5 to 10 and results in death by the late teens or 20s. Santavuori-Haltia disease affects children 6 months to 2 years old and results in death by 5 years old. Jansky-Bielschowsky disease affects children from 2 to 4 years old and results in death generally between 8 and 12 years old. Kufs disease affects adults and isn't considered fatal. All of these conditions are characterized by progressive loss of sight and seizures that don't respond to conventional medical treatments.

Carcinoid Symptoms:

Carcinoid tumors can cause life-threatening symptoms from both hormone hypersecretion (over production) as well as tumor growth and invasion.

The majority of individuals with carcinoid tumors are asymptomatic until the tumors metastasize to the liver and cause symptoms of tumor secretion. However, as the tumors grow they can cause obstructive symptoms.

Obstructive Symptoms: 

Midgut and Hindgut

Individuals with midgut and (in rare cases) hindgut carcinoids may experience symptoms such as abdominal pain, nausea, and vomiting, even though diagnostic scanning shows nothing. Many individuals diagnosed with liver metastases have reported having undiagnosed abdominal pain for several years prior to their diagnosis of carcinoid.

**Foregut**

Individuals with bronchial (lung) carcinoids most commonly present with obstructive symptoms. These symptoms may include chronic lung infection such as bronchitis and pneumonia, breathing difficulties, chest pain, and chronic cough (Kulke, 2007; Fink, Krelbaum, Yellin, Bendayan, Saute, Glazer, & Kramer 2001). Less commonly, symptoms may include weakness, nausea, sweating, and Cushing's Syndrome (Fink et al., 2001; Granberg, Winlander, Oberg, & Skogseid, 2000).

**Carcinoid Syndrome**

Carcinoid tumors can secrete a variety of hormones which can cause many clinical symptoms such as flushing and diarrhea. Symptoms occurring together may be classified as a syndrome. Carcinoid Syndrome occurs in approximately 10% of individuals with carcinoid tumors and is most commonly found in individuals with midgut carcinoid tumors that have metastasized to the liver (Poncet, Faucheron, & Walter, 2010). In midgut carcinoid tumors, carcinoid syndrome does not normally develop until the tumors have metastasized since the liver is able to break down the excess hormones produced by these tumors (Kulke, 2007). However, once the tumors develop in the liver, the liver is no longer able to break down the excess hormones, and symptoms from them may occur. Carcinoid tumors that develop outside of the midgut can cause carcinoid syndrome without liver metastases, but rarely do.

**Typical Carcinoid Syndrome**

Typical Carcinoid Syndrome is the most common form of Carcinoid Syndrome and is most often caused by midgut carcinoids that have metastasized to the liver. Excess serotonin is the hormone most frequently related to Carcinoid Syndrome. The syndrome is characterized by brief episodes of flushing, diarrhea, cough, wheezing, shortness of breath, heart disease, and in rare cases, pellagra. Flushing and diarrhea are the two main symptoms that are associated with Carcinoid Syndrome. Diarrhea can be mild to severe which may lead to weight loss and life style changes. The flushing may be light pink to a deep red and occurs in the face and in the nipple-line. It may be triggered by stress, alcohol, exercise and certain types of foods.

**Atypical Carcinoid Syndrome**

Atypical Carcinoid Syndrome is rare and is associated with foregut carcinoid tumors. It is characterized by extended episodes of flushing, headache, shortness of breath, and in rare cases, lacrimation (tears) (Tomassetti, Migliori, Lalli, Campana, Tomasetti, & Corinaldesi, 2001). The flushing can be deep purple and last for hours. It may be followed by increased blood flood to the limbs (arms and legs) and to the trunk (chest, stomach and back). This flush is not brought on by food (Tomassetti et al., 2001).

**Carcinoid Crisis**

Individuals with Carcinoid Syndrome can also experience Carcinoid Crisis which can occur spontaneously or be stress induced. A Carcinoid Crisis can be a life-threatening event that requires careful monitoring. Symptoms of a Carcinoid Crisis may include severe hypotension or hypertension, irregular and/or rapid heartbeat, wheezing, prolonged flushing, severe dyspnea (shortness of breath), and peripheral cyanosis (lack of oxygenated blood).

**Carcinoid Heart Disease**

Carcinoid tumors can secrete a variety of hormones and vasoactive substances such as serotonin. When these substances are released from liver metastases, the right side of the heart is exposed to them. As a result, patients may experience Carcinoid Heart Disease characterized by plaque lesions in the right side of the heart. Carcinoid Heart Disease can cause right-sided heart failure (Connolly, Modesto, Moller, Pellikka, Seward, & Rubin 2003). Carcinoid Heart Disease is most common on the right side of the heart but can also occur on the left side (Smith 1968). While serotonin production is related to development of Carcinoid Heart Disease, there is evidence of increased cardiac lesions during somatostatin analog therapy (Moller, Connolly, Rubin, Seward, Modesto, & Pelikka, 2003). All carcinoid cancer patients should be familiar with Carcinoid Heart Disease and discuss appropriate monitoring with their physician.

**Cushing's Syndrome**

Bronchial (lung) carcinoid tumors can also secrete the adrenocorticotropic hormone (ACTH) which may cause Cushing's Syndrome. Cushing's Syndrome is characterized by excessive upper body weight gain, skin disorders (bruising and poor healing), baldness, and psychological disorders such as depression and anxiety.

**Zollinger-Ellison Syndrome**

Gastrinomas hypersecrete (over produce) gastrin causing Zollinger-Ellison Syndrome. Symptoms of Zollinger-Ellison Syndrome include diarrhea and peptic-ulcers. Patients with Zollinger-Ellison Syndrome may also develop gastric carcinoid as a result of prolonged gastrin hypersecretion.

**Cushing's disease**

Cushing's disease is a condition in which the pituitary gland releases too much adrenocorticotropic hormone (ACTH). The pituitary gland is an organ of the endocrine system. Cushing's disease is a form of Cushing's syndrome.

Cushing's disease is caused by a tumor or excess growth (hyperplasia) of the pituitary gland. This gland is located at the base of the brain.

People with Cushing's disease have too much ACTH. ACTH stimulates the production and release of cortisol, a stress hormone. Too much ACTH means too much cortisol.

Cortisol is normally released during stressful situations. It controls the body's use of carbohydrates, fats, and proteins and also helps reduce the immune system's response to swelling (inflammation).

Symptoms:

Symptoms usually include:

1. Upper body obesity (above the waist) and thin arms and legs

2. Round, red, full face (moon face)

3. Slow growth rate in children

Skin changes that are often seen:

1. Acne or skin infections

2. Purple marks (1/2 inch or more wide), called striae, on the skin of the abdomen, thighs, and breasts

3. Thin skin with easy bruising

Muscle and bone changes include:

1. Backache, which occurs with routine activities

2. Bone pain or tenderness

3. Collection of fat between the shoulders (buffalo hump)

4. Thinning of the bones, which leads to rib and spine fractures

5. Weak muscles

6. Women often have:

7. Excess hair growth on the face, neck, chest, abdomen, and thighs

8. Menstrual cycle that becomes irregular or stops

Men may have:

1. Decreased or no desire for sex

2. Impotence

Other symptoms that may occur include:

1. Mental changes, such as depression, anxiety, or changes in behavior

2. Fatigue

3. Headache

4. Increased thirst and urination

Gout Symptoms and Signs

The first symptom of gouty arthritis is typically the sudden onset of a hot, red, swollen joint. The most common joint involved is at the base of the big toe where swelling can be associated with severe tenderness, but almost any joint can be involved (for example, knee, ankle, and small joints of the hands). In some people, the acute pain is so intense that even a bed sheet on the toe causes severe pain. Acute gouty arthritis at the base of the big toe is referred to as podagra.

Even without treatment, the first attacks stop spontaneously after one to two weeks. While the pain and swelling completely go away, gouty arthritis commonly returns in the same joint or in another joint.

With time, attacks of gouty arthritis can occur more frequently and may last longer. While the first attacks usually involve only one or two joints, multiple joints can be involved simultaneously over time. It is important to note that unrecognizable (subclinical), potentially damaging inflammation in joints can occur between attacks of obvious flares of gouty arthritis.

Kidney stones are more frequent in people with gout.

Uric acid crystals can form outside joints. Collections of these crystals, known as tophi, can be found in the earlobe, elbow, and Achilles tendon (back of the ankle), or in other tissues. Typically, these tophi are not painful but can be a valuable clue for the diagnosis as the crystals that form them can be removed with a small needle for microscopic examination. Microscopic evaluation of a tophus reveals a nest-like accumulation of uric acid crystals embedded with white blood cells of inflammation

**Celiac disease**

Celiac Disease can appear at any time in a person's life. In adults, the disease can be triggered for the first time after surgery, viral infection, severe emotional stress, pregnancy or childbirth. CD is a multi-system, multi-symptom disorder. Symptoms vary and are not always gastrointestinal (GI). GI symptoms can often mimic other bowel disorders.

Infants, toddlers and young children with CD may often exhibit growth failure, vomiting, bloated abdomen, behavioral changes and failure to thrive.

Classic symptoms may include:

Abdominal cramping, intestinal gas

Distention and bloating of the stomach

Chronic diarrhea or constipation (or both)

Steatorrhea – fatty stools

Anemia – unexplained, due to folic acid, B12 or iron deficiency (or all)

Unexplained weight loss with large appetite or weight gain

Other symptoms: 

Dental enamel defects

Osteopenia, osteoporosis

Bone or joint pain

Fatigue, weakness and lack of energy

Infertility – male/female

Depression

Mouth ulcers

Delayed puberty

Tingling or numbness in hands or feet

Migraine headaches

**Aspergillosis**

Aspergillosis is a lung disease that develops after inhaling spores of Aspergillus fungi. Disease-causing species of Aspergillus are common in the environment but usually cause illness only in individuals with a weakened immune system. The disease takes three forms: allergic bronchopulmonary aspergillosis, aspergilloma and invasive aspergillosis. According to the Mayo Clinic, "These illnesses, collectively called aspergillosis, range from allergic responses to severe and sometimes fatal infections." Allergic bronchopulmonary aspergillosis results from inhaling Aspergillus spores, which triggers an asthmatic reaction. Aspergilloma is a fibrous growth of fungus that develops in the lung tissue. Invasive aspergillosis is a rare but serious form of aspergillosis. In this disease, a widespread fungal infection occurs throughout the lungs.

**Legionnaires' Disease**

Scientists first described the rare bacterial condition known as legionnaires' disease in 1976 after an epidemic of severe pneumonia broke out among veterans at an American Legion convention in Philadelphia. Although the bacterium that causes the disease is found in virtually all water supplies, it thrives in large, water-cooled air-conditioning systems and accumulates in plumbing systems where water stagnates. Legionnaires' disease is three times more common in men than in women and has its highest incidence in those aged 40 to 70, especially if they are smokers, diabetics, or alcoholics or if they are taking drugs that suppress the immune system.

**Berylliosis**

According to the National Institute of Environmental Health Sciences, beryllium disease is rare but continues to occur in individuals employed in industries where berylium is used, such as the fluorescent lighting industry and in the production of nuclear reactors. The effects of acute berylliosis include fibrosis and pulmonary edema. Fibrosis is scarring of the lung tissue, and pulmonary edema is a buildup of fluid in the lungs. Both conditions impede oxygen and carbon dioxide exchange in the lungs. Symptoms of chronic berylliosis are breathlessness, coughing, chest pain and joint pain.

**Primary Ciliary Dyskinesia**

The condition affects the tiny hair-like structures, called cilia, that extend from various cells in the body, and causes a range of symptoms: persistent lung, sinus and ear infections, male infertility, and sometimes a reversed orientation of major organs in the body.

Primary ciliary dyskinesia is difficult to diagnose and requires a high degree of suspicion. It is inherited, so scientists and doctors are doing DNA tests to help the children who may have inherited the disease.

The researchers found the error in a gene, HEATR2, which had never been linked to primary ciliary dyskinesia or to cilia. It brings the number of genes associated with the disorder to 15, but they are still thought to account for fewer than half of all cases of the disorder.

In healthy people, hair-like extensions called cilia that sit atop cells beat rapidly – roughly 10 times a second – to clear inhaled pollutants and bacteria from the lungs, nose and middle ear.

Typically, newborns with the disorder have respiratory distress shortly after birth and may need the help of a ventilator to breathe. As they grow, the children develop persistent cough. Runny or stuffy noses and respiratory infections are common year round.

The wide-ranging symptoms can be traced to defects in cilia that sit atop cells lining the respiratory tract, from the nose to the airsacs of the lungs. Cilia normally beat rapidly – roughly 10 times a second – to clear inhaled pollutants and bacteria from the lungs, nose and middle ear.

Early in development, cilia also move fluid across the embryo's surface and detect signals that indicate where the heart, lungs, spleen and other internal organs should be placed. Sperm sport similar structures, called flagella, that propels their movement.

But in patients with primary ciliary dyskinesia, the cilia don't beat effectively if at all. In many patients, the cilia clearly look defective under an electron microscope. However, cilia can appear normal in some patients. The newly identified mutation in HEATR2 changes the structure of cilia and affects the microscopic motors that power them to beat.

**Anthrax**

Anthrax is a life-threatening infectious disease that normally affects animals, especially ruminants (such as goats, cattle, sheep, and horses). Anthrax can be transmitted to humans by contact with infected animals or their products. In recent years, anthrax has received a great deal of attention as it has become clear that the infection can also be spread by a bioterrorist attack or by biological warfare. Anthrax does not spread from person to person.

The agent of anthrax is a bacterium called Bacillus anthracis. While other investigators discovered the anthrax bacillus, it was a German physician and scientist, Dr. Robert Koch, who proved that the anthrax bacterium was the cause of a disease that affected farm animals in his community. Under the microscope, the bacteria look like large rods. However, in the soil, where they live, anthrax organisms exist in a dormant form called spores. These spores are very hardy and difficult to destroy. The spores have been known to survive in the soil for as long as 48 years.

Anthrax can infect humans in three ways. The most common is infection through the skin, which causes an ugly sore that usually goes away without treatment. Humans and animals can ingest anthrax from carcasses of dead animals that have been contaminated with anthrax. Ingestion of anthrax can cause serious, sometimes fatal disease. The most deadly form is inhalation anthrax. If the spores of anthrax are inhaled, they migrate to lymph glands in the chest where they proliferate, spread, and produce toxins that often cause death.

**Morgellons**

Today, Morgellons stands as a very poorly understood disease that some doctors seem to believe if a chronic infectious disease. Sadly, the disease is usually disfiguring as well as disabling. The disease is classified by biting, itching, or crawling sensations, filaments that grow from the skin, and skin lesions, as well as memory loss, joint paint, and fatigue. Morgellons is still not recognized by the entire medical community, but there have been about 2,000 people within the U.S. who believe they suffer from the disease. Some of the reports are children, who are said to be unable to do normal things such as going to school or playing sports. There is no known cure or effective treatment for Morgellons.

**Paraneoplastic pemphigus (PNP)**

Though there are many forms of pemphigus, paraneoplastic pemphigus is the least common and most serious. PNP is a rare autoimmune bullous disease that causes blistering. Keratinocytes, which are what make up the epidemus, separate from each other, leaving gaps. Many times the gaps become filled with fluid peel off, leaving the skin raw and open to infection. These blisters usually appear in the mouth, throat, lips, and random places on the skin. The disease is also extremely fatal, as 90% of those diagnosed with the disease die due to sepsis, multi-organ failure, or cancer that caused the disease.

**Microcephaly**

Microcephaly is a very rare condition that is noticeable immediately at birth, and sometimes even before. It affects 1 in every 666,666 in the U.S. With microcephaly, the brain is unable to develop properly, or in some cases ceases to grow at all, while the baby is still in the womb. This causes the head to be smaller than a normal infant's head at birth. Many believe that the disease is caused by exposure to harmful substances while in the womb, exposure to radiation, or genetic problems. The disease is usually paired with Down's syndrome. Those who have microcephaly are usually mentally retarded and will have issues with hyperactivity, dwarfism, seizures, balance issues, speech and motor problems, as well as others.

**Von Hippel-Lindau (VHL)**

Von Hippel-Lindau disease (VHL) is said to affect one in 35,000 people. It is an extremely rare genetic condition that is characterized by the growth of tumors in different parts of the body. Many of the tumors will grow within the central nervous system and are often benign, but are made of blood vessels. Medically known as hemangioblastomas, these tumors can start to grow in the retina, the brain, and the spinal cord. Different tumors are also known to grow on the pancreas, adrenal glands, and kidneys. If left untreated, the disease can cause strokes, heart attacks, and cardiovascular disease.

**Kuru**

As rare as it is, Kuru is one disease that is fatal. However, it is so rare that the disease is confined to an area in New Guinea, more specifically the Fore tribe that lives in the highlands. The disease came about as a result of cannibalism, which is a ritualistic practice in which the tissues of others, especially the brain, were cooked and consumed. Those affected with the disease usually become unable to eat or stand, and then about 6-12 months later die in a comatose state. It is said that about 1,100 people died from Kuru during the 1950s and 60s. Because of government intervention and a wide-spread effort to end cannibalism, Kuru has now mostly disappeared.

**Fibrodysplasia ossificans progressiva (FOP)**

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease that affects the connective tissue. The disease is said to only affect 1 in 2 million people. Around the world there have been 700 confirmed cases of the disease, 285 of those being in the U.S. FOP is classified when the body causes fibrous tissue, such as ligament, muscle, and tendons, to become ossified, or to change into bone when damaged. This means that a fall can cause bone to grow within the muscles and tendons throughout the body. FOP stands as the only disease known that causes one type of organ system to turn into an entirely different one. At birth, the classic symptom of the disease is a malformation of the big toe. There is no known treatment for FOP, as surgery to get rid of the bone, seems to cause the body to produce even more.

**Fields' disease**

Fields' disease is said to be the rarest disease in the world. It is named after two twins, Catherine and Kirstie Fields from Wales. The disease doesn't have a medical name, but doctors have been able to call it a neuromuscular disease. The muscles within the body slowly deteriorate, which limits movements. The girls' disease has been studied by doctors from all over. Because the disease is so rare and unknown, doctors aren't sure what will happen next. The disease has since limited the lives of the girls, binding them to wheelchairs and making a simple task such as writing, hard.

**Hutchinson-Gilford Progeria**

Usually known as just Progeria, this condition is one that only affects one in about 8 million children born. Most born with the condition only live to be about 13, while others have been able to live into their early twenties. Progeria is a genetic condition that occurs due to a new mutation characterized by the dramatic, rapid appearance of aging beginning in childhood. In most cases, the disease is not inherited, though there has been a case of a similar condition where the parents carry the protein genetically and then pass it on to their children. There is no cure for Progeria, though doctors have tried growth hormone treatment as well as anticancer drugs. Usually doctors try to focus on reducing complications of the disease.

**Polio**

First known and recognized in 1840, polio is a disease that is spread from person to person, or through the means of contaminated food or water. Most cases of polio exhibit no symptoms, unless the disease is introduced through the blood stream. In most cases, polio causes paralysis and muscle weakness. Though a widely spread disease during the early 90's, polio has since became eradicated in 36 countries. In 2002 Europe stated that it has no seen a case of polio since the poliovirus vaccine. Only four countries in the world as of 2006 still consider polio to be an endemic.

**Bubonic Plague**

This plague is transmitted through infected fleas and kills about 70 percent of its victims in 4-7 days. The most well known epidemic was the Black Death in Medieval times when it was rumored to have killed about 25 million in Europe alone and another 50 million across the world. The bubonic plague is often characterized by swollen lymph nodes though the modern world has seen few breakouts.

**The Plague Of Athens**

The Plague of Athens was an epidemic that broke out in Greece during the Peloponnesian War in 430 BC. Historians have been unable to agree on exactly what the plague was, with typhoid, smallpox, and measles all being considered, but it is most commonly considered to have been a form of the bubonic plague. The disease started when the inhabitants of Athens retreated behind the city-state's walls for protection from the approaching Spartan army. The cramped quarters inevitably became a breeding ground for the plague, which is said to have killed one in three of the city-state's inhabitants, including its leader, Pericles.

**The Antonine Plague**

Now suspected to have been an outbreak of measles or smallpox, the Antonine Plague was a pandemic that ravaged the Roman Empire from 165 to 180 AD. Also known as the Plague of Galen, the disease is suspected to have been brought to Rome by troops returning from battle. It is estimated that at its height the Antonine Plague killed a quarter of all the people it infected, as many as 5 million in all, and victims included two of Rome's emperors. In 251 AD, a similar sickness broke out, which many believe to have been a return of the Plague of Antonine. This time it was known as the Plague of Cyprian, and at its height it is said that the disease was killing 5,000 people a day in the city of Rome.

**Typhus**

Known for its ability to spread quickly in cramped and unsanitary conditions, typhus is credited with millions of deaths in the 20th century alone. The disease is also known as "camp sickness" for the way it seems to flare up on the front lines during wartime. It is said that 8 million Germans were killed by a typhus pandemic during the 30 years war, and the disease is also well documented as a significant cause of death in Nazi concentration camps. Typhus is perhaps most famously known for nearly wiping out the French army during Napoleon's invasion of Russia. It has been estimated that as many as 400,000 of his soldiers may have died from the disease, many more than were killed in combat.

**The Spanish Flu**

Arriving on the heels of the devastation of World War I, the Spanish Flu of 1918 is widely considered to be one of the most vicious pandemics in history. A worldwide phenomenon, it is estimated to have infected one third of the world's entire population, and eventually killed as many as 100 million people. The virus, which has since been identified as a strain of H1N1, would surface in waves, frequently disappearing in communities as quickly as it arrived. Fearing a massive uproar, governments did their best to downplay the severity of the flu, and because of wartime censorship, its far-reaching effects were not fully realized until years later. Only Spain, a neutral country during WWI, allowed comprehensive news reporting on the pandemic, which is why it eventually became known as the Spanish Flu.

**Pediatric Autoimmune Neuropsychiatric Disorders Associated with a froup A beta-hemolytic Streptococcal infection (PANDAS)**

PANDAS is an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with a group A beta-hemolytic Streptococcal infection and applied to a subgroup of children with obsessive-compulsive disorder (OCD) and/or tic disorders. The prevalence is unknown but the boy-to-girl ratio is 2.6:1. The current diagnostic criteria for the PANDAS are: presence of OCD and/or a tic disorder, very young age at onset (prepubertal), sudden and dramatic onset of symptoms, association between streptococcal infections and episodic relapsing-remitting exacerbations manifesting as neuropsychiatric symptoms (motor hyperactivity or adventitious movements including choreiform movements or tics). The increased severity of symptoms usually persists for at least several weeks, but may last for several months or longer, followed by a slow, gradual improvement. The major distinctive feature of PANDAS is the temporal association between neuropsychiatric symptom exacerbations and streptococcal infections. Additional neuropsychiatric symptoms occur frequently: emotional lability, separation anxiety, anorexia, impulsivity, distractibility and motor hyperactivity characteristic of attention deficit hyperactivity disorder (ADHD). Comorbid disorders include major depression (36%), major dysthymia (6%) and separation anxiety disorder (20%). The etiology is uncertain. One theory is that streptococcal infections trigger an antibody response in some children that causes changes in the basal ganglia. No specific genetic factors have been identified. Diagnosis of PANDAS is clinical. Neuroimaging studies may reveal increased basal ganglia volumes. Management includes standard interventions for obsessive-compulsive and tic disorders: cognitive-behavioural therapy, reversal therapy in the case of tic disorders and pharmacologic therapy (neuropsychiatric drugs, antibiotics to prevent infections and intravenous immunoglobulin therapy).

**Rasmussen Syndrome**

A rare autoimmune brain disorder that is caused by inflammation of brain cells in one hemisphere. Rasmussen syndrome, whose cause is unknown, features seizures that can be difficult or impossible to control with medication, and it eventually results in brain shrinkage (atrophy). Treatment is surgery, if possible. The half of the brain affected by the disease will be removed and may cause permanent paralysis or death if not treated right away. The inflammation seems to stop of its own accord eventually, but the damage done is irreversible.

**Aase-Smith syndrome I**

A syndrome of congenital malformations (birth defects) characterized by hydrocephalus, cleft palate, and severe arthrogryposis (joint contractures). Other anomalies may include deformed ears, ptosis (drooping) of the eyelids, inability to open the mouth fully, heart defects, and clubfoot. The fingers are thin with absent knuckles, reduced creases over the joints and inability to make a full fist.

The syndrome is inherited as an autosomal dominant trait, transmitted from generation to generation, affecting both males and females. It is named for the American dysmorphologists (birth-defect experts) Jon Aase and David W. Smith.

**Aplastic anemia**

Anemia due to failure of the bone marrow to produce red and white blood cells as well as platelets. Aplastic anemia frequently occurs without a known cause. Known causes include exposure to chemicals (for example, benzene, toluene in glues, insecticides, solvents), drugs (for example, chemotherapy drugs, gold, seizure medications, antibiotics), viruses (for instance, HIV, Epstein-Barr), radiation, immune conditions (for example, systemic lupus erythematosus, rheumatoid arthritis), pregnancy, paroxysmal nocturnal hemoglobinuria, and inherited disorders (for example, Fanconi anemia).

**Blackfan-Diamond Anemia**

Blackfan-Diamond anemia (DBA) is a congenital aregenerative and often macrocytic anemia with erythroblastopenia. Annual incidence in the general population of Europe is estimated at around 1/150,000. Both sexes are equally affected and no ethnic predisposition has been identified. The anemia is discovered early in life, usually within the first 2 years; diagnosis after 4 years of age is very unlikely. Pallor and dyspnea, especially during feeding or while sucking, are the principal warning signs. Pallor is isolated, without organomegaly, signs suggestive of hemolysis or involvement of other hematopoietic cell lines. Over half of all DBA patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Pregnancies in DBA-affected women are now identified as high-risk, for both mother and child. DBA patients may also be at a higher risk of leukemia and cancer. DBA is inherited as an autosomal dominant trait with variable penetrance. At present, disease-causing mutations are identified in 40-45% of patients. All involved genes code for ribosomal proteins (RPs) from either the small (_RPS7_, _RPS17_, _RPS19_, _RPS24_) or the large (_RPL5_,_RPL11_, _RPL35a_) ribosomal subunit. Mutations in _RPS19_, _RPL5_ and _RPL11_ are found in 25%, 9% and 6.5% of patients respectively, whereas the other genes are each involved in only 1 to 3% of cases. The only clear genotype/phenotype correlation made so far is the frequent occurrence of craniofacial abnormalities in _RPL5_ and_RPL11_ mutation carriers and the rarity of these anomalies in _RPS19_ mutation carriers. In a child with anemia and erythroblastopenia, the diagnosis can be supported by a familial history (10-20% of cases), associated malformations (40% of cases), and elevated erythrocyte adenosine deaminase (EAD), which is a frequent but non-specific sign that may also be elevated in relatives in the absence of other DBA symptoms. Detection of a disease-causing mutation is of diagnostic value. The differential diagnosis should include transient erythroblastopenia (see this term), chronic parvovirus B19 infection, and other congenital anemias. Genetic counseling and prenatal diagnosis are difficult because of the variability of clinical expression and the fact that only 40-45% of patients have an identified mutation within a RP gene. In familial cases, the risk of recurrence is 50%. Close ultrasound follow-up during the pregnancy is recommended in all cases. The two main therapeutic approaches are regular transfusions and long-term corticosteroid therapy. Treatment must be adapted to each case and according to the age of the patient. Steroids should not be administered during the first year of life. Short stature, occurring both as part of the syndrome and due to treatment-related complications (steroids, hemochromatosis), is a major issue for these patients. Allogenic bone-marrow transplantation must be discussed in corticoresistant patients when an unaffected and HLA-identical sib is available. The prognosis is generally good. However, complications of treatment and a higher incidence of cancer may reduce life expectancy. Disease severity depends on the quality and response to treatment. For patients undergoing regular transfusions, quality of life is clearly altered.

**Fanconi Anemia**

Fanconi anemia (FA) is a hereditary DNA repair disorder characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors.

Recent determination of the carrier frequency gave an estimate of more than 1/200, with an expected prevalence at birth of at least 1/160,000. In certain populations, the carrier frequency is much higher, due to founder mutations. Until now, more than 2,000 cases have been reported in the literature.

In 2/3 of patients, the first signs of FA are congenital malformations that may involve the skeleton, skin, uro-genital, cardio-pulmonary, gastrointestinal and central nervous systems. Limb anomalies are unilateral or bilateral, the latter being frequently asymmetrical. Minor anomalies can also be present such as low height and weight, microcephaly and/or microphthalmia. Skin pigmentation abnormalities and hypoplastic thenar eminence are frequent. Almost 20% of patients have ear malformations with or without hearing loss. Congenital malformations may vary in a family. When congenital malformations are not prominent, diagnosis may be delayed until the onset of bone marrow failure (BMF), which occurs at a median age of 7 years. Hematologic abnormalities may occur at a younger age and, more rarely, in adults, with 90% of patients developing BMF by 40 years of age. Patients may develop acute myeloid leukemia, often preceded by myelodysplastic syndrome. Patients are also highly predisposed to solid tumors, of the head and neck or anogenital regions. Short stature is often secondary to hormonal deficiencies. Fertility is almost totally impaired in males, and is highly disturbed in half of females. Pregnancy is often complicated.

FA is due to mutations in genes involved in DNA repair and genomic stability. Fifteen genes representing 15 complementation groups have been identified.

Given the high heterogeneity in genetic causation and clinical phenotype, and the pathogenic mechanism of FA, diagnosis relies on the evaluation of chromosomal breakage induced by diepoxybutane (DEB) or mitomycin C (MMC).

FA clinical manifestations overlap with many malformation syndromes (Dubowitz, Seckel, Holt-Oram, Baller-Gerold, thrombocytopenia-absent radius, Nijmegen breakage syndromes, VACTERL association, dyskeratosis congenita; see these terms) and diagnosis of FA is often delayed until a patient develops BMF or malignancies. FA should be considered in the differential diagnosis of all young patients with BMF of unknown etiology. Other cancer predisposition syndromes (Bloom, Rothmund-Thomson or Werner syndromes; see these terms) or syndromes with pancytopenia (Diamond-Blackfan anemia, immune pancytopenia, Pearson or Shwachman-Diamond syndromes; see these terms) should be considered.

Prenatal diagnosis is feasible with a DEB-induced chromosomal breakage assay or by molecular study when the mutation is known.

FA is usually an autosomal recessive disorder but X-linked transmission may occur.

Supportive care includes transfusions of packed red blood cells (RBC) or leucodepleted platelets. The only curative treatment for hematologic manifestations is hematopoietic stem cell transplantation (HSCT). However, this approach tends to increase the solid tumor risk, which must be specially monitored. Symptomatic treatment includes oral androgen administration, which improves blood counts in some patients, in particular RBC. Administration of hematopoietic growth factor could be considered after bone marrow aspirate and biopsy, which should be regularly performed during the treatment. When malignancies develop, treatment is complicated by the sensitivity to radiation and chemotherapy of FA patients.

BMF and malignancies lead to a poor prognosis with a reduced life expectancy, which has been improved by HSCT and androgen treatment.

**Warm antibody hemolytic anemia**

Warm antibody hemolytic anemia is an autoimmune disorder characterized by the premature destruction of healthy red blood cells by autoantibodies. Autoimmune diseases occur when the body's natural defenses against foreign organisms (e.g., lymphocytes, antibodies) destroy healthy tissue for unknown reasons. Normally, red blood cells have a life span of approximately 120 days before they are removed by the spleen. The medical term for low levels of circulating red blood cells is anemia. Anemia may cause fatigue, a pale skin color (pallor), yellowing of the skin and whites of the eyes (jaundice) and the passage of blood in the urine (hemoglobinuria), which gives the urine a dark brown color. Warm antibody hemolytic anemia is classified as an autoimmune hemolytic anemia (AIHA), an uncommon group of disorders in which the immune system mistakenly attacks healthy red blood cells.

**Hereditary nonspherocytic hemolytic anemia**

Hereditary nonspherocytic hemolytic anemia is a term used to describe a group of rare, genetically transmitted blood disorders characterized by the premature destruction of red blood cells (erythrocytes or RBCs). If the red blood cells cannot be replaced faster than they destroy themselves, anemia is the result.

In these disorders, the outside membrane of the cell is weakened, causing it to have an irregular, non-spherical shape and to burst (hemolyze) easily. These disorders are caused by, among other things, defects in the chemical processes involved in the breakdown of sugar molecules (glycolysis). Red blood cells depend on this process for energy and if an enzyme is defective in any one of the stages, the red blood cell cannot function properly and hemolysis, or the breakdown of the membrane that holds the cell together, takes place. The more common of the enzyme deficiencies that lead to HNSHA involve glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency and hexokinase deficiency. There may be as many as 16 red blood cell enzyme abnormalities that may cause hereditary nonspherocytic hemolytic anemia. In addition, HNSHA may arise as the result of immune disorders, toxic chemicals and drugs, antiviral agents (eg, ribavirin), physical damage, and infections.

**Hereditary Spherocytic Anemia**

Hereditary spherocytic hemolytic anemia is a rare blood disorder characterized by defects within red blood cells (intracorpuscular) that result in a shortened survival time for these cells. Red blood cells (erythrocytes) normally circulate for a few months and when they die off are replaced by new erythrocytes. However, in hereditary spherocytic hemolytic anemia, the cells die prematurely. They also have low amounts of fats (lipid) in the cell membranes and an abnormally small amount of surface area. The red blood cells are sphere-shaped (spherocytic) making it difficult for them to pass through the spleen, resulting in the early destruction of these cells (hemolysis). The sphere shape of the red blood cells is the hallmark of this disorder, and this abnormality may be identified under a microscope. Hereditary spherocytic hemolytic anemia is caused by an inherited metabolic defect.

**Megaloblastic Anemia**

Megaloblastic anemia is a condition in which the bone marrow produces unusually large, structurally abnormal, immature red blood cells (megaloblasts). Bone marrow, the soft spongy material found inside certain bones, produces the main blood cells of the body -red cells, white cells, and platelets. Anemia is a condition characterized by the low levels of circulating, red blood cells. Red blood cells are released from the marrow into the bloodstream where they travel throughout the body delivering oxygen to tissue. A deficiency in healthy, fully-matured red blood cells can result in fatigue, paleness of the skin (pallor), lightheadedness and additional findings. Megaloblastic anemia has several different causes - deficiencies of either cobalamin (vitamin B12) or folate (vitamin B9) are the two most common causes. These vitamins play an essential role in the production of red blood cells.

**Pernicious Anemia**

Pernicious anemia is a rare blood disorder characterized by the inability of the body to properly utilize vitamin B12, which is essential for the development of red blood cells. Most cases result from the lack of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed.

The symptoms of pernicious anemia may include weakness, fatigue, an upset stomach, an abnormally rapid heartbeat (tachycardia), and/or chest pains. Recurring episodes of anemia (megaloblastic) and an abnormal yellow coloration of the skin (jaundice) are also common. Pernicious anemia is thought to be an autoimmune disorder, and certain people may have a genetic predisposition to this disorder.

There is a rare congenital form of pernicious anemia in which babies are born lacking the ability to produce effective intrinsic factor. There is also a juvenile form of the disease, but pernicious anemia typically does not appear before the age of 30. The onset of the disease is slow and may span decades. When the disease goes undiagnosed and untreated for a long period of time, it may lead to neurological complications. Nerve cells and blood cells need vitamin B12 to function properly.

**Angioedema**

Hereditary angioedema is a rare inherited disorder characterized by recurrent episodes of the accumulation of fluids outside of the blood vessels, blocking the normal flow of blood or lymphatic fluid and causing rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. Usually, this swelling is not accompanied by itching, as it might be with an allergic reaction. Swelling of the gastrointestinal tract leads to cramping. Swelling of the airway may lead to obstruction, a potentially very serious complication. These symptoms develop as the result of deficiency or improper functioning of certain proteins that help to maintain the normal flow of fluids through very small blood vessels (capillaries). In some cases, fluid may accumulate in other internal organs. The severity of the disease varies greatly among affected individuals.

The most common form of the disorder is hereditary angioedema type I, which is the result of abnormally low levels of certain complex proteins in the blood (C1 esterase inhibitors), known as complements. They help to regulate various body functions (e.g., flow of body fluids in and out of cells). Hereditary angioedema type II, a more uncommon form of the disorder, occurs as the result of the production of abnormal complement proteins.

**Antithrombin III Deficiency**

Antithrombin deficiency is a blood disorder characterized by the tendency to form clots in the arteries and/or veins (thrombosis). An inherited tendency to thrombosis is known as thrombophilia. Antithrombin is a substance in the blood that limits the blood's ability to clot (coagulation). In people with congenital antithrombin deficiency, there is usually a reduced amount of this substance in the blood due to a genetic abnormality. Antithrombin deficiency may also be acquired; in such cases, the disorder may be reversible with treatment.

**Cor Triatriatum**

Cor triatriatum is an extremely rare congenital (present at birth) heart defect. Normally, the human heart has four chambers of which two are the atria. These two are separated from each other by a partition (septum) called the atrial septum. The other two chambers, known as ventricles, are also separated by a septum. In cor triatriatum there is a small extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra "third atrium." The passage of blood from the lungs into the heart (left atrium and ventricle) is slowed by this extra chamber. Cor triatriatum may eventually lead to features of congestive heart failure and obstruction over time.

**Edema, Idiopathic**

Idiopathic Edema is a common disorder that occurs almost exclusively in women. It is characterized by salt retention in the absence of heart, kidney, or liver disease. The swelling (edema) may be episodic or persistent. Swelling of the face, hands, and feet develops rapidly, frequently accompanied by headache, irritability, and depression. Weight gain also occurs.

**Idiopathic dilatation of PA**

Idiopathic dilatation of the pulmonary artery (IDPA) is a rare congenital defect characterized by a wider than normal main pulmonary artery in the absence of any apparent anatomical or physiological cause.

**Endocardial Fibroelastosis (EFE)**

Endocardial fibroelastosis (EFE) is a rare heart disorder that affects infants and children. It is characterized by a thickening within the muscular lining of the heart chambers due to an increase in the amount of supporting connective tissue (inelastic collagen) and elastic fibers. The normal heart has four chambers. Two chambers, known as atria, are separated from each other by a partition called the atrial septum. The other two chambers, known as ventricles, are also separated by a septum. Valves connect the atria (left and right) to their respective ventricles.

The symptoms of endocardial fibroelastosis are related to the overgrowth of fibrous tissues causing abnormal enlargement of the heart (cardiac hypertrophy), especially the left ventricle. Impaired heart and lung function eventually lead to congestive heart failure. Endocardial fibroelastosis may occur for no apparent reason (sporadic) or may be inherited as an X-linked (EFE2) or autosomal recessive (EFE1) genetic trait.

**Factor XIII Deficiency**

Factor XIII Deficiency is an extremely rare inherited blood disorder characterized by abnormal blood clotting that may result in abnormal bleeding. Associated symptoms and findings occur as the result of a deficiency in the blood clotting factor F13A1 (Factor XIII). In affected individuals, the blood fails to clot appropriately, resulting in poor wound healing. Blood may seep into surrounding soft tissues, resulting in local pain and swelling. Internal bleeding may occur; approximately 25 percent of affected individuals experience bleeding in the brain (intracranial hemorrhage). Factor XIII Deficiency may be inherited as an autosomal dominant genetic trait. The disease may also be acquired in association with other disorders such as Sickle Cell Disease or Henoch-Schonlein Purpura.

**Heart Block, Congenital**

Congenital heart block is characterized by interference with the transfer of the electrical nerve impulses (conduction) that regulate the normal, rhythmic, pumping action of the heart muscle (heart block). The severity of such conduction abnormalities varies among affected individuals.

The normal heart has four chambers. The two upper chambers are the atria and the two lower chambers are the ventricles. Within the right atrium of a normal heart is a natural pacemaker that initiates and controls the heartbeat. The electrical stimulus travels from the pacemaker (sinoatrial or SA node) to the ventricles along a very specific path consisting of conducting tissue and known as the AV (atrioventricular) node. As long as the electrical impulse is transmitted normally, the heart behaves normally.

If the transmission of the signal is impeded, the blocked transmission is known as a heart block or an AV block. If the heart block occurs in the fetus or newborn, the condition is known as congenital heart block. This condition has nothing at all to do with the flow of blood or with the blockage of a major or minor coronary artery. It is an electrical problem rather than a hydraulic one.

Heart blocks are categorized according to the degree of impairment of the patient. The categories are first, second and third degree heart block.

**Hemangioma Thrombocytopenia**

Kasabach-Merritt phenomenon is a rare association of profound thrombocytopenia associated with two rare vascular tumors: kaposiform hemangioendotheliomas and tufted angiomas. The profound thrombocytopenia can cause life threatening bleeding and progress to a disseminated coagulopathy in patients with these tumors.

**Hemorrhagic Telangiectasia**

Hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome) is a rare inherited disorder characterized by malformations of various blood vessels (vascular dysplasia), usually resulting in excessive bleeding (hemorrhaging). Chronic nosebleeds are often the first apparent symptom associated with hereditary hemorrhagic telangiectasia. Malformation of various blood vessels may result in abnormalities affecting various organ systems of the body including the lungs, brain, and liver. Hereditary hemorrhagic telangiectasia is inherited as an autosomal dominant trait.

**Hypoplastic Left Heart Syndrome**

Hypoplastic left heart syndrome is a term used to describe a group of closely related rare heart defects that are present at birth (congenital). The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. The valves allow for blood to be pumped through the chambers. Blood travels from the right ventricle through the pulmonary artery to the lungs where it receives oxygen. The blood returns to the heart through pulmonary veins and enters the left ventricle. The left ventricle sends the now oxygen-filled blood into the main artery of the body (aorta). The aorta sends the blood throughout the body.

Hypoplastic left heart syndrome is characterized by the underdevelopment (hypoplasia) of the chambers on the left side of the heart (i.e., left atrium and ventricle). In addition, the mitral valve, which connects these chambers to each other, is usually abnormally narrow (stenosis) or closed (atresia) and the aortic valve, which connects the heart to the major vessels that lead from the lungs (ascending aorta), may also be narrow or closed. Infants with hypoplastic left heart syndrome also have an abnormally narrow ascending aorta.

**Idiopathic Pulmonary Fibrosis**

Idiopathic pulmonary fibrosis is an inflammatory lung disorder of unknown origin (idiopathic) characterized by abnormal formation of fibrous tissue (fibrosis) between the tiny air sacs (alveoli) or ducts of the lungs. Coughing and rapid, shallow breathing occur with moderate exercise. The skin may appear slightly bluish (cyanotic) due to lack of circulating oxygen. Complications such as infection, emphysema or heart problems may develop.

**Lymphedema, Hereditary**

Hereditary lymphedema is a genetic developmental disorder affecting the lymphatic system. It is characterized by swelling (edema) of certain parts of the body. The lymphatic system is a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich fluid (lymph) and blood cells throughout the body. In hereditary lymphedema, lymphatic fluid collects in the soft tissues in and under the skin (subcutaneous) due to obstruction, malformation, or underdevelopment (hypoplasia) of various lymphatic vessels. There are three forms of hereditary lymphedema: congenital hereditary lymphedema or Milroy disease; lymphedema praecox or Meige disease; and lymphedema tarda. Symptoms include swelling (lymphedema) and thickening and hardening of the skin in affected areas. In most cases, hereditary lymphedema is inherited as an autosomal dominant trait.

Lymphedema may be considered primary or secondary. Hereditary lymphedema is also known as primary lymphedema. Secondary lymphedema occurs because of damage to the lymphatic system from surgery, radiation therapy, trauma or an underlying condition**.**

**Maffucci Syndrome**

Maffucci syndrome is an extremely rare disorder characterized by benign overgrowths of cartilage (enchondromas), skeletal deformities, and dark red, irregular shaped patches of skin, resulting from benign growths on the skin consisting of a mass of blood vessels (hemangiomas). Enchondromas are most often found in certain bones (phalanges) of the hands and feet. Skeletal malformations may include legs that are disproportionate in length. In many cases, bones may tend to fracture easily. Hemangiomas usually appear during early childhood and may be progressive. The exact cause of Maffucci syndrome is unknown.

**Perniosis**

Perniosis is an inflammatory disorder that is triggered by prolonged exposure to cold and damp (humid) conditions. It is a form of inflammation of the small blood vessels (vasculitis) and is characterized by painful, itchy, tender, skin lesions on the lower legs, hands, toes, feet, ears and face. The lesions usually last for two to three weeks. One form of the disorder affects the blood vessels of the thighs.**Polycythemia Vera**

Polycythemia vera is a rare, chronic disorder involving the overproduction of blood cells in the bone marrow (myeloproliferation). The overproduction of red blood cells is most dramatic, but the production of white blood cells and platelets are also elevated in most cases. Since red blood cells are overproduced in the marrow, this leads to abnormally high numbers of circulating red blood cells (red blood mass) within the blood. Consequently, the blood thickens and increases in volume, a condition called hyperviscosity. Thickened blood may not flow through smaller blood vessels properly. A variety of symptoms can occur in individuals with polycythemia vera including nonspecific symptoms such as headaches, fatigue, weakness, dizziness or itchy skin; an enlarged spleen (splenomegaly); a variety of gastrointestinal issues; and the risk of blood clot formation, which may prevent blood flow to vital organs. More than 90 percent of individuals with polycythemia vera have a mutation of the JAK2 gene. The exact role that this mutation plays in the development of polycythemia vera is not yet known.

Polycythemia vera was first reported in the medical literature in 1892. The term "myeloproliferative disorder" (MPD) was first used to described polycythemia vera and related disorders in 1951. In 2008, the World Health Organization reclassified MPDs to "myeloproliferative neoplasms" (MPNs) to reflect the consensus that these diseases are blood cancers (neoplasms).

This group of disorders is characterized by the overproduction (proliferation) of one or more of the three main blood cell lines - red or white blood cells or platelets. Red blood cells carry oxygen to the body. White blood cells fight infection. Platelets are involved in clotting of the blood in response to injury. Three other disorders are commonly classified as MPNs: chronic myeloid leukemia, essential thrombocythemia and idiopathic myelofibrosis. Because MPNs are characterized by uncontrolled cell growth, they may also be classified as blood cancers.

**Mantle Cell Lymphoma**

Mantle cell lymphoma (MCL) belongs to a group of diseases known as non-Hodgkin's lymphomas, which are related malignancies (cancers) that affect the lymphatic system (lymphomas). Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.

As lymph moves through the lymphatic system, it is filtered by a network of small structures known as lymph nodes that help to remove microorganisms (e.g., viruses, bacteria, etc.) and other foreign bodies. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Lymphocytes are stored within lymph nodes and may also be found in other lymphatic tissues. In addition to the lymph nodes, the lymphatic system includes the spleen, which filters worn-out red blood cells and produces lymphocytes, and the tonsils, which are masses of lymphoid tissue in the throat region that help to fight infection. Lymphatic tissues also include the thymus, a relatively small organ behind the breastbone that is thought to play an important role in the immune system until puberty, as well as the bone marrow, which is the spongy tissue inside the cavities of bones that manufactures blood cells. Lymphatic tissue or circulating lymphocytes may also be located in other regions of the body, such as the skin, small intestine, liver, and other organs. There are two main types of lymphocytes: B-lymphocytes, which may produce specific antibodies to "neutralize" certain invading microorganisms, and T-lymphocytes, which may directly destroy microorganisms or assist in the activities of other lymphocytes.

Mantle cell lymphoma and other cancers of the lymphatic system (lymphomas) result from errors in the production of a lymphocyte or transformation of a lymphocyte into a malignant cell. Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions; involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from case to case, depending upon the extent and region(s) of involvement and other factors.

Non-Hodgkin's lymphomas (NHLs) may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) and those derived from abnormal T-lymphocytes (T-cell lymphomas). Mantle cell lymphoma (MCL) is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. NHLs may also be categorized based upon certain characteristics of the cancer cells as seen under a microscope and how quickly they may tend to grow and spread. For example, NHLs may be characterized as "low-grade" (or indolent) lymphomas, which tend to grow slowly and result in few associated symptoms, or "intermediate-" or "high-grade" (aggressive) lymphomas, which typically grow rapidly, requiring prompt treatment. There is some debate concerning whether MCL should be categorized as a slow-growing (indolent) or rapidly-growing (aggressive) lymphoma. Although experts have classified MCL as an aggressive lymphoma, it has been shown to have certain characteristics of indolent lymphoma.

According to various estimates, MCL represents approximately 2 to 7 percent of adult NHLs in the United States and Europe. It primarily affects men over the age of 50 years. Many affected individuals have widespread disease at diagnosis, with involved regions often including multiple lymph nodes, the spleen, and, potentially, the bone marrow, the liver, and/or regions of the digestive (gastrointestinal) tract.

**Pure Red Cell Aplasia, Acquired**

Acquired Pure Red Cell Aplasia is a rare bone marrow disorder characterized by an isolated decline of red blood cells (erythrocytes) produced by the bone marrow. Affected individuals may experience fatigue, lethargy, and/or abnormal paleness of the skin (pallor). Acquired Pure Red Cell Aplasia may occur for unknown reasons (idiopathic) or as a primary autoimmune disorder. It is also believed that Acquired Pure Red Cell Aplasia may occur secondary to a tumor of the thymus gland (thyoma), viral infections, or certain drugs.

**Pyruvate Kinase Deficiency**

Red cell pyruvate kinase deficiency is a hereditary blood disorder characterized by a deficiency of the enzyme pyruvate kinase. Physical findings associated with the disorder may include reduced levels of oxygen-carrying hemoglobulin in the blood due to premature destruction of red blood cells (hemolytic anemia); abnormally increased levels of bilirubin in the blood (hyperbilirubinemia); abnormal enlargement of the spleen (splenomegaly); and/or other abnormalities. Pyruvate kinase deficiency is inherited as an autosomal recessive genetic trait. It is one of a group of diseases known as hereditary nonspherocytic hemolytic anemias. (Nonspherocytic refers to the fact that the red blood cells do not assume a spherical shape, as they do with some blood disorders.

**Thalassemia Minor**

Thalassemia Minor is a rare blood disorder characterized by a moderately low level of hemoglobin in red blood cells (anemia). This disorder is inherited. People with Thalassemia Minor have one of a pair (heterozygous) of the thalassemia gene. If a person has two copies of the gene, they will have Thalassemia Major, which is a more serious disease.

**Vitamin B12 Deficiency**

Vitamin B12 has many important functions in the body. It works with the B vitamin folate to make our body's genetic material. It helps keep levels of the amino acid homocysteine in check, which may help decrease heart disease risk, and it is essential to the production of red blood cells, which carry oxygen through the blood to the body's tissues.

But many people are deficient in this important vitamin.

Causes of Vitamin B12 Deficiency

Vitamin B12 deficiency can have a number of possible causes. Typically it occurs in people whose digestive systems do not adequately absorb the vitamin from the foods they eat. This can be caused by:

Pernicious anemia, a condition in which there is a lack of a protein called intrinsic factor. The protein, which is made in the stomach, is necessary for vitamin B12 absorption.

Atrophic gastritis, a thinning of the stomach lining that affects up to 30% of people aged 50 and older.

Surgery in which part of the stomach and/or small intestine is removed.

Conditions affecting the small intestine, such as Crohn's disease, celiac disease, bacterial growth, or a parasite.

Excessive alcohol consumption.

Autoimmune disorders, such as Graves' disease or systemic lupuserythematosus

Long-term use of acid-reducing drugs.

Vitamin B12 deficiency can also occur in vegetarians, because the best food sources of the vitamin are animal products. Strict vegans (people who don't eat any animal products, including meat, eggs, or milk) are at greatest risk. Vegetarians who eat eggs and milk products are also at risk, because, on average, they consume less than half the adult Recommended Dietary Allowance (RDA) of vitamin B12.

Babies born to mothers who are vegetarians may also be deficient in vitamin B12.

Symptoms of Vitamin B12 Deficiency

A deficiency of vitamin B12 can lead to vitamin B12 deficiency anemia. A mild deficiency may cause only mild, if any, symptoms. But as the anemia worsens it may causes symptoms such as:

weakness, tiredness or light-headedness

rapid heartbeat and breathing

pale skin

sore tongue

easy bruising or bleeding, including bleeding gums

stomach upset and weight loss

diarrhea or constipation

If the deficiency is not corrected, it can damage the nerve cells. If this happens, vitamin B12 deficiency effects may include:

tingling or numbness in fingers and toes

difficulty walking

mood changes or depression

memory loss, disorientation, and dementia

B12 deficiency in infants, if not detected and treated, can lead to severe and permanent damage to the nervous system. New mothers who follow a vegetarian diet should have their babies' B12 levels checked by a doctor.

Treatment for Vitamin B12 Deficiency

Vitamin B12 deficiency treatment depends on the cause of the deficiency. If pernicious anemia or a problem with absorption is the cause, B12 replacement will be necessary. Most often this is given by injection; some people may be prescribed vitamin tablets.

For some people, B12 supplementation may be necessary for life. If a diet lacking in animal products is the cause, the doctor will recommend dietary changes along with supplementation of vitamin B12 by injection or tablet.

For most people, treatment resolves the anemia; however, any nerve damage that has occurred as a result of the deficiency could be permanent.

Preventing Deficiency Problems

Most people can prevent vitamin B12 deficiency by consuming enough meat, poultry, seafood, milk, cheese, and eggs. If you don't eat animal products or you have a medical condition that limits your absorption of nutrients, experts recommend taking a B12-containing multivitamin and eating breakfast cereal fortified with vitamin B12.

If you experience symptoms of B12 deficiency, speak to your doctor about a blood test to check B12 levels.

**Waldenstrom's Macroglobulinemia**

Waldenstrom's macroglobulinemia (WMG) is a malignant disorder of the blood, closely related to lymphoma and characterized by the presence of abnormally large numbers of a particular kind of white blood cell known as B lymphocytes. As these cells accumulate in the body, excessive quantities of an antibody known as IgM are produced. This causes the blood to become thick (hyperviscosity) and affects the flow of blood through the smaller blood vessels, leading to the symptoms of the disorder. The organs fed by these small blood vessels do not receive sufficient blood and oxygen, potentially resulting in partial or complete failure of the organ.

**Cri du chat syndrome**

Cri du chat syndrome (CdCS or 5p-) is a rare genetic disorder in which a variable portion of the short arm of chromosome 5 is missing or deleted (monosomic). Symptoms vary greatly from case to case depending upon the exact size and location of the deleted genetic material. Common symptoms include a distinctive cry that resembles the mewing of a cat, characteristic facial features, slow growth, and microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant's age and sex. Affected children also exhibit delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor disability) and moderate to severe intellectual disability. Additional symptoms affecting different organ systems of the body can also occur. Most cases are thought arise from spontaneous (de novo) genetic errors very early in embryonic development.

**Cystic fibrosis**

Cystic fibrosis is a genetic disorder that often affects multiple organ systems of the body. Cystic fibrosis is characterized by abnormalities affecting certain glands (exocrine) of the body especially those that produce mucus. Saliva and sweat glands may also be affected. Exocrine glands secrete substances through ducts, either internally (e.g., glands in the lungs) or externally (e.g., sweat glands). In cystic fibrosis, these secretions become abnormally thick and can clog up vital areas of the body causing inflammation, obstruction and infection. The symptoms of cystic fibrosis can vary greatly in number and severity from one individual to another. Common symptoms include breathing (respiratory) abnormalities including a persistent cough, shortness of breath and lung infections; obstruction of the pancreas, which prevents digestive enzymes from reaching the intestines to help break down food and may result in poor growth and poor nutrition; and obstruction of the intestines. Cystic fibrosis is slowly progressive and often causes chronic lung damage, which eventually results in life-threatening complications. Because of improved treatments and new treatment options, the outlook and overall quality of life of individuals with cystic fibrosis has improved and more than 40 percent of individuals with the disorder are adults. Cystic fibrosis is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is inherited as an autosomal recessive trait.

**Duchenne muscular dystrophy**

Duchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3500 male births worldwide. It is usually recognized between three and six years of age. DMD is characterized by weakness and wasting (atrophy) of the muscles of the pelvic area followed by the involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve additional muscles of the body. The disorder is progressive and most affected individuals require a wheelchair by the teen-age years. Serious life-threatening complications may ultimately develop including disease of the heart muscle (cardiomyopathy) and breathing (respiratory) difficulties.

DMD is caused by changes (mutations) of the DMD gene on the short arm (p) of the X chromosome. The gene regulates the production of a protein called dystrophin that is found in association with the membrane of skeletal and cardiac muscle cells. Dystrophin is thought to play an important role in maintaining the structure of these muscle cells. DMD is classified as a dystrophinopathy. The dystrophinopathies are a spectrum of muscle diseases, each caused by alterations in DMD gene. The severe end of the spectrum is known as Duchenne muscular dystrophy and the less severe as Becker muscular dystrophy.

The dystrophinopathies belong to a large group of diseases known as the muscular dystrophies. These disorders are characterized by specific changes (e.g. variation of muscle fiber size, muscle fiber necrosis and inflammation) in muscle biopsy. The clinical hallmarks include the weakness and wasting of various voluntary muscles of the body. Approximately 30 different disorders make up the muscular dystrophies. The disorders affect different muscles and have different ages of onset, severity and inheritance patterns.

Aceruloplasminemia Aceruloplasminemia is a rare genetic disorder characterized by the abnormal accumulation of iron in the brain and various internal organs. Affected individuals develop neurological symptoms including cognitive impairment and movement disorders. Degeneration of the retina and diabetes may also occur. Symptoms usually become apparent during adulthood between 20 and 60 years of age. Aceruloplasminemia is caused by mutations of the ceruloplasmin (CP) gene. This mutation is inherited as an autosomal recessive trait.

Aceruloplasminemia is classified as a Neurodegenerative disorder with Brain Iron Accumulation (NBIA). NBIA are a group of rare inherited disorders characterized by iron accumulation in the brain. Aceruloplasminemia is also classified as an iron overload disorder.

**GRACILE syndrome**

GRACILE syndrome is characterised by foetal growth retardation (G), aminoaciduria (A), cholestasis (C), iron overload (I), lactacidosis (L), and early death (E). The syndrome affects principally the Finnish population, in which the incidence is approximately 1 in 47 000. It is transmitted in an autosomal recessive manner. The causative gene has been identified as _BCS1L _(chromosome 2q33-37), which encodes a mitochondrial inner membrane protein.

**Progeria**

Progeria, or Hutchinson-Gilford progeria syndrome (HGPS), is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small nose; prominent eyes and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin(subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. According to reports in the medical literature, individuals with HGPS develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years. As with any person suffering from heart disease, the common events as heart disease advances for children with progeria can include high blood pressure, strokes, angina (chest pain due to poor blood flow to the heart itself),enlarged heart, and heart failure, all conditions associated with aging.

Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria.

**Congenital ****Atransferrinemia**

Atransferrinemia is an extremely rare genetic disorder characterized by low levels of healthy, functional red cells in the blood (hypochromic, microcytic anemia) and by the accumulation of excess iron in the body (hemosiderosis). Symptoms may vary based upon the severity of anemia and upon the extent of iron accumulation in the body and the specific organs affected. Common symptoms include recurrent infections and growth delays. Atransferrinemia is principally caused by mutations of the transferrin (TF) gene and is inherited as an autosomal recessive trait. Atransferrinemia is classified as an iron overload disorder. A milder form of atransferrinemia, known as hypotransferrinemia, is caused by mutations in the same gene.

**Prader-Willi syndrome**

Prader-Willi syndrome (PWS) is a genetic disorder characterized by low muscle tone, short stature if not treated with growth hormone, incomplete sexual development, and a chronic feeling of hunger that, coupled with a metabolism that utilizes drastically fewer calories than normal, can lead to excessive eating and life-threatening obesity. The food compulsion makes constant supervision necessary. Average IQ is 70, but even those with normal IQs almost all have learning issues. Social and motor deficits also exist. At birth the infant typically has low birth weight for gestation, hypotonia (weak muscles), and difficulty sucking due to the hypotonia which can lead to a diagnosis of failure to thrive. The second stage ("thriving too well"), has a typical onset between the ages of two and five, but can be later. The hyperphagia (extreme unsatisfied drive to consume food) lasts throughout the lifetime. Children with PWS have sweet and loving personalities, but this phase is also characterized by increased appetite, weight control issues, and motor development delays along with some behavior problems and unique medical issues.

**Tay-Sachs disease**

Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. This disorder is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or "digest" nutrients, including certain complex carbohydrates and fats.

Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy; an adult form (late-onset Tay-Sachs disease) may occur anytime from adolescence to the mid 30s.

Tay-Sachs disease is inherited as an autosomal recessive trait. The disorder results from changes (mutations) of a gene known as the HEXA gene, which regulates production of the hexosaminidase A enzyme. The HEXA gene has been mapped to the long arm (q) of chromosome 15 (15q23-q24).

**Achondroplasia**

Achondroplasia is a rare genetic disorder characterized by an unusually large head (macrocephaly) with a prominent forehead (frontal bossing) and flat (depressed) nasal bridge; short upper arms and legs (rhizomelic dwarfism), unusually prominent abdomen and buttocks; and short hands with fingers that assume a "trident" or three-pronged position during extension. An autosomal dominant genetic trait, achondroplasia occurs as a result of a fresh (new) spontaneous change (mutation) in genetic material in about 90 percent of cases. In achondroplasia, affected individuals have impaired ability to form bone from cartilage (endochondral bone formation).

**Phenylalanine hydroxylase**

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and is characterized by mild to severe mental disability in untreated patients.

The prevalence of PKU shows considerable geographic variation. It is estimated to be 1/10,000 live births in Europe with a higher rate in some countries (Ireland, Italy). Prevalence is particularly high in Turkey: 1/4,000 live births. PKU is far rarer in the Finnish, African and Japanese populations.

In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty odor. Untreated patients subsequently develop intellectual disability, behavioral disorders (hyperactivity) and motor disorders. Patients often have fair coloring as a result of tyrosine deficiency. The most common form of the condition is known as classical phenylketonuria (see this term) and is characterized by severe symptoms. A mild form has also been described (mild PKU; see this term), and an even milder form known as mild hyperphenylalaninemia (mild HPA or non-PKU HPA; see this term). A subset of patients with milder phenotypes has been found to be responsive to tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylation (BH4-responsive HPA, see this term).

PKU is caused by a wide range of mutations in the _PAH_ gene (12q22-q24.2) coding for phenylalanine hydroxylase. Non-_PAH_ mutations have been reported to cause a disorder known as hyperphenylalaninemia due to BH4 deficiency (see this term). Mutation frequency varies among different ethnic groups. Lower levels or absence of the phenylalanine hydroxylase enzyme underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain.

The disorder is usually diagnosed through neonatal screening programs.

PKU should be distinguished from BH4 deficiency.

Transmission is autosomal recessive. Genetic counseling should be provided to affected families.

The mainstay of treatment is a low-phenylalanine diet and amino acids mixture for the forms that require treatment. The recommended maintenance level is usually between 120 and 360 micromol/L in newborns, with treatment considered essential in older patients with levels above 600 micromol/L. There is, however, no consensus concerning the level of phenylalanine above which treatment should be initiated and recommendations vary from country to country.

Other definition:

Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life with appropriate blood testing (e.g., during routine neonatal screening). PKU is characterized by absence or deficiency of an enzyme (phenylalanine hydroxylase) that is responsible for processing the essential amino acid phenylalanine. (Amino acids, the chemical building blocks of proteins, are essential for proper growth and development.) With normal enzymatic activity, phenylalanine is converted to another amino acid (tyrosine), which is then utilized by the body. However, when the phenylalanine hydroxylase enzyme is absent or deficient, phenylalanine abnormally accumulates in the blood and is toxic to brain tissue.

Symptoms associated with PKU are typically absent in newborns. Affected infants may be abnormally drowsy and listless (lethargic) and have difficulties feeding. In addition, untreated infants with PKU tend to have unusually light eyes, skin, and hair (light pigmentation) and may develop a rash that appears similar to eczema, an inflammatory skin condition that may be characterized by itching, redness, and blistering in affected areas.

Without treatment, most infants with PKU develop mental retardation that is typically severe. Those with untreated PKU may also develop additional neurologic symptoms, such as episodes of uncontrolled electrical activity in the brain (seizures), abnormally increased activity (hyperactivity), poor coordination and a clumsy manner of walking (gait), abnormal posturing, aggressive behavior, or psychiatric disturbances. Additional symptoms and findings may include nausea, vomiting, and a musty or "mousy" body odor due to the presence of a by-product of phenylalanine (phenylacetic acid) in the urine and sweat.

To prevent mental retardation, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life. Most experts suggest that a phenylalanine-restricted diet should be lifelong in persons with classical PKU. Classical PKU refers to persons with 2 severe mutations of the phenylalanine hydroxylase gene.

**Sirenomelia Sequence (Mermaid Syndrome)**

Sirenomelia Sequence is a birth defect in which affected infants are born with a single lower extremity or with two legs that are fused together. Due to the wide range of possible physical deformities that may occur, the symptoms and physical findings associated with Sirenomelia Sequence vary greatly from case to case.

**Hemophilia**

Hemophilia is a rare inherited blood clotting (coagulation) disorder caused by inactive or deficient blood proteins (usually factor VIII). Factor VIII is one of several proteins that enable the blood to clot. Hemophilia may be classified as mild, moderate, or severe. The level of severity is determined by the percentage of active clotting factor in the blood (normal percentage ranges from 50 to 150 percent). People who have severe hemophilia have less than one percent of active clotting factor in their blood.

There are three major types of hemophilia: hemophilia A (also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); hemophilia B (Christmas disease or factor IX deficiency); and hemophilia C (factor XI deficiency). Hemophilia A and B are inherited as X-linked recessive genetic traits, while Hemophilia C is inherited as an autosomal recessive genetic trait. Therefore, while hemophilia A and B are fully expressed in males only, hemophilia C affects males and females in equal numbers.

**Scleroderma**

Scleroderma is a rare autoimmune connective tissue disorder characterized by abnormal thickening of the skin. Connective tissue is composed of collagen, which supports and binds other body tissues. There are several types of scleroderma. Some types affect certain, specific parts of the body, while other types can affect the whole body and internal organs (systemic). Scleroderma is also known as progressive systemic sclerosis. The exact cause of scleroderma is unknown.

**Sweets syndrome**

Sweet syndrome is a rare skin disorder characterized by fever, inflammation of the joints (arthritis), and the sudden onset of a rash. The rash consists of bluish-red, tender papules that usually occur on the arms, legs, face or neck, most often on one side of the body (asymmetric). In approximately 80 percent of cases, Sweet syndrome occurs by itself for no known reason (idiopathic). In 10 to 20 percent of cases, the disorder is associated with an underlying malignancy, usually a hematologic malignancy such as certain types of leukemia. The exact cause of Sweet syndrome is unknown.

**Urticaria Pigmentosa**

Urticaria pigmentosa is a rare skin disorder that is a localized (cutaneous) form of mastocytosis. Some clinicians suggest that urticaria pigmentosa is the childhood form of mastocytosis. Mast cells are specialized cells of connective tissue that release substances such as histamine (a chemical important in the inflammatory process) and heparin (an anti-clotting agent) when the body's alarm mechanism is set off. When mast cells cluster and multiply excessively (proliferate), histamine and heparin are released into the skin (mastocytosis). The characteristic skin lesions of urticaria pigmentosa appear in these areas. Urticaria pigmentosa is generally benign and is usually self-limited. The exact cause of the disease is not known, although some cases may be inherited.

**Dermatitis herpetiformis**

Dermatitis herpetiformis, also known as Duhring disease, is a rare, chronic, skin disorder characterized by the presence of groups of severely itchy (pruritic) blisters and raised skin lesions (papules). These are more common on the knees, elbows, buttocks and shoulder blades. The exact cause of this disease is not known although it is frequently associated with the inability to digest gluten (gluten sensitive enteropathy [GSE] or celiac sprue).

**Xeroderma-pigmentosum**

Xeroderma pigmentosum (XP) is a group of rare inherited skin disorders characterized by a heightened reaction to sunlight (photosensitivity) with skin blistering occurring after exposure to the sun. In some cases, pain and blistering may occur immediately after contact with sunlight. Acute sunburn and persistent redness or inflammation of the skin (erythema) are also early symptoms of XP. In most cases, these symptoms may be apparent immediately after birth or occur within the next three years. In other cases, symptoms may not develop until later in childhood or, more rarely, may not be recognized until adulthood. Other symptoms of XP may include discolorations, weakness and fragility, and/or scarring of the skin.

Xeroderma pigmentosum affects the eyes as well as the skin, has been associated with several forms of skin cancer, and, in some cases, may occur along with dwarfism, mental retardation, and/or delayed development.

Several subtypes of XP (i.e., XP complementation groups) have been identified, based upon different defects in the body's ability to repair DNA damaged by ultraviolet light (UV). According to the medical literature, the symptoms and findings associated with the classic form of xeroderma pigmentosum, known as XP, type A (XPA), may also occur in association with the other XP subtypes. These include: XP, type B (XPB); XP, type C (XPC), XP, type D (XPD); XP, type E (XPE); XP, type F (XPF); and XP, type G (XPG). These XP subtypes are transmitted as an autosomal recessive trait. In addition, another subtype of the disorder, known as XP, dominant type, has autosomal dominant inheritance.

In addition to the XP subtypes discussed above, researchers have identified another form of the disorder known as XP, variant type (XP-V). As with the other XP subtypes, symptoms and findings associated with the classic form of XP may also be seen in individuals with XP-V. XP-V cells have a normal or near normal ability to repair UV-induced DNA damage (nucleotide excisional repair), however, they are defective in replicating UV-damaged DNA during the division and reproduction of cells. Although the disorder's mode of inheritance is unknown, most researchers suspect that XP-V is transmitted as an autosomal recessive trait.

**Goltz syndrome**

Goltz syndrome or focal dermal hypoplasia is characterized by a polymorphic cutaneous disorder and highly variable anomalies affecting the eyes, teeth, skeleton and the central nervous, urinary, gastrointestinal and cardiovascular systems. The prevalence is unknown. Clinical signs constitute areas of cutaneous atrophy and periorificial papillomas that predominate around the mouth, genitalia and/or anus. Subcutaneous fatty tissue may herniate where small atrophic areas meet. Other typical findings include onychodystrophy and cicatricial alopecia. Skeletal disorders are observed at birth, with syndactyly, ectodactyly and/or aplastic fingers and toes. Osseous defects include scoliosis, hypoplastic clavicles and ribs, and a deformed thorax. As a rule, dental anomalies are associated and may include malpositioned teeth, extra teeth and enamel defects. Eyes are classically affected by coloboma of the iris, microphthalmia, and/or strabismus. Psychomotor retardation may also be present. The syndrome affects tissues deriving from the ectoderm and the mesoderm. It is transmitted as an X-linked dominant trait and is lethal _in utero_ in male fetuses, causing high miscarriage rates in affected families. The gene causing the disease has not yet been identified but a deletion in the short arm of the X chromosome, with the point of rupture at Xp22.31, has been identified in some patients and may represent the localization of the genetic lesion. Differential diagnosis should be made with Hoffmann-Zurhelle naevus, incontinentia pigmenti, and congenital poikilodermias. Treatment is symptomatic, involving dermatological and orthopedic care. The papillomas may require surgical intervention. Individuals with severe forms of the syndrome usually die during infancy but many of the other patients have a normal life expectancy.

**Harlequin Ichthyosis**

Harlequin ichthyosis is a rare genetic skin disorder. The newborn infant is covered with plates of thick skin that crack and split apart. The thick plates can pull at and distort facial features and can restrict breathing and eating. Harlequin infants need to be cared for in the neonatal intensive care unit immediately. Harlequin ichthyosis is inherited as an autosomal recessive trait.

**Morgellon's disease**

Morgellons disease is the popular name for an unexplained skin disorder characterized by disfiguring sores and crawling sensations on and under the skin. Morgellons disease also features fibers or solid materials emerging from these sores.

People who have Morgellons disease report the following signs and symptoms:

Skin rashes or sores that can cause intense itching

Crawling sensations on and under the skin, often compared to insects moving, stinging or biting

Fibers, threads or black stringy material in and on the skin

Severe fatigue

Difficulty concentrating

Short-term memory loss

The intense itching and open sores associated with Morgellons disease can severely interfere with a person's quality of life.

Morgellons disease is a relatively rare condition that most frequently affects middle-aged white women. A cluster of cases occurred in California, which prompted the CDC to conduct a research study to determine if the cases were somehow related.

Morgellons disease is caused by an infectious agent or a substance in the environment. Researchers studied samples of skin, blood, urine and hair. Half of the hair samples tested positive for drugs such as marijuana, anti-anxiety medications or painkillers containing codeine derivatives.

Skin lesions most closely resembled insect or spider bites that had been worsened by scratching. The most commonly affected sites were the forearms, back, chest, face and lower legs. Some of the lesions were infected by germs commonly found on the skin, but these infections were not the cause of the lesions. No parasites were detected.

**Physical Urticaria (Aquagenic Pruritus)**

Physical urticaria is a condition in which red (erythematous) allergic skin lesions and itching (pruritus) are produced by exposure to heat, cold, or contact with chemicals or plants. These are called wheals by the medical community and may range in size from a couple of millimeters to a couple of centimeters. The center of the lesion may range in color from white to red, and it is usually surrounded by a flare of red skin. The disorder occurs most commonly in children.

**Morgellons**

Morgellons is a controversial and poorly understood condition in which unusual thread-like fibers appear under the skin. The patient may feel like something is crawling, biting, or stinging all over.

Some medical experts say Morgellons is a physical illness. Others suggest it is a type of psychosis called "delusional parasitosis," in which a person thinks parasites have infected their skin.

Your doctor may call it an "unexplained dermopathy," which means a skin condition that occurs without a known reason. Other medical professionals have dubbed the condition "fiber disease."

Symptoms of Morgellons

Unpleasant skin sensations are the main complaint. People with Morgellons may also complain of:

Feeling like bugs are crawling all over the skin.

Burning or stinging sensations under the skin.

Intense itching.

Skin sores that appear suddenly and heal slowly.

Sores that leave very red (hyperpigmented) scars.

Some patients report thread-like fibers stuck in the skin.

People with Morgellons sometimes complain of other symptoms which may include:

Difficulty paying attention and concentrating

Extreme fatigue

Hair loss

Joint and muscle pain

Nervous system problems

Tooth loss

Sleep problems

Short-term memory loss

Treatment of Morgellons

There is no known cure for Morgellons. Treating any medical or psychiatric problems that occur at the same time as Morgellons may help ease Morgellons symptoms in some patients.

A team of medical researchers at the Mayo Clinic also recommend that patients with these symptoms should undergo psychiatric evaluation.

Who Gets Morgellons

In the past, few doctors had heard of Morgellons. But in response to scattered reports, the CDC worked together with several other health care agencies to investigate this condition. Most reports came from California, Texas, and Florida, although patients have been seen in all 50 states.

The CDC study found that Morgellons is most likely to affect middle-aged white women.

Many of the patients in the CDC study showed signs of being obsessively concerned about health problems in general. This is called somatic concerns.

About half of the people in the study had other health problems, including depression and drug abuse.

The Debate Over Morgellons

The question of whether Morgellons is a disease or a delusion has prompted debate and new research in recent years.

The CDC states that the condition is not caused by an infection or anything in the environment.

The CDC study also included a lab analysis of skin fibers in Morgellons patients. The analysis showed that these fibers were mostly cotton, such as typically found in clothing or bandages.

CDC research also revealed that the skin sores seemed to be the result of long-term picking and scratching the skin.

The CDC report goes on to say: "We were not able to conclude, based on this study, whether this unexplained dermopathy represents a new condition, as has been proposed by those who use the term Morgellons, or wider recognition of an existing condition such as delusional parasitosis."

Previous case studies and research have suggested that Morgellons may be linked to Lyme disease. Some patients with signs and symptoms of Morgellons had tested positive for the bacteria that causes Lyme disease.

But according to Morgellons researchers at Oklahoma State University, there is no evidence to prove this theory. Likewise, there was no evidence of Lyme infection in any of the people in the CDC study.

A 2010 study found a potential link between Morgellons symptoms and an underactive thyroid (hypothyroidism). More research needs to be done to further investigate this finding.

Morgellons appears similar to a condition seen in cattle called bovine digital dermatitis, which is due to an infection, according to a 2011 study. The study researchers say this provides evidence that Morgellons is not a delusional disorder.

**Albinism**

Oculocutaneous albinism is a group of rare inherited disorders characterized by a reduced amount or complete lack of melanin pigment in the skin, hair, and eyes. These conditions are caused by mutations in specific genes that are necessary for the production of melanin pigment. Abnormal or insufficient melanin pigmentresults in vision abnormalities and light skin that is very susceptible to damage from the sun. Oculocutaneous albinism is inherited as an autosomal recessive genetic condition.

**Porphyrias**

Porphyria is a group of disorders that can cause nerve or skin problems.

A porphyria that affects the skin is called cutaneous porphyria. A porphyria that affects the nervous system is called acute porphyria.

The most common type of porphyria is porphyria cutanea tarda (PCT), which affects the skin. PCT is also the most treatable.

No known cure exists for any type of porphyria.

Symptoms of Acute Porphyria

The symptoms of acute porphyria can develop quickly and last for days or weeks. A salt imbalance sometimes accompanies an episode of this type of porphyria. The imbalance can contribute to some of these symptoms:

Chest pain

Abdominal pain, often severe

Increased heart rate and blood pressure

Limb and back pain

Muscle weakness

Tingling

Loss of sensation

Cramping

Vomiting and constipation

Personality changes or mental disorders

Agitation, confusion, and seizures

Long-term complications in some patients have included:

Chronic pain

Depression

Kidney damage

Liver cancer

Symptoms of Cutaneous Porphyria

Symptoms of cutaneous porphyria occur when the skin is exposed to sunlight. The most commonly affected areas include the back of the:

Hands

Forearms

Face

Ears

Neck

The symptoms include:

Blisters

Itching

Swelling of the skin

Pain

Increased hair growth

Darkening and thickening of the skin

Causes of Porphyria

Each type of porphyria has the same root cause - a problem in the production of heme. Heme is a component of hemoglobin. That's a protein in red blood cells that carries oxygen from the lungs to the rest of the body.

Heme contains iron and gives blood its red color. The production of heme takes place in the liver and bone marrow and involves eight different enzymes. A shortage of any of those enzymes can create an excess buildup of certain chemical compounds involved in producing heme. The specific type of porphyria is determined by which enzyme is lacking.

Most types of porphyria are inherited. About half of them occur when one altered gene is passed from just one parent. The risk of developing a porphyria or passing it to your children depends on the specific type.

Porphyria cutanea tarda, on the other hand, is often an acquired disease. Although the enzyme deficiency that causes PCT can be inherited, most people who inherit it never develop symptoms. Instead, the disease becomes active when the deficiency is triggered by certain conditions or lifestyle choices. These include:

Drinking alcohol

Excessive intake of iron

Hepatitis C

HIV

Smoking

Episodes of acute porphyria, which very rarely occur before puberty, can be triggered by some drugs. These include:

Barbiturates

Tranquilizers

Birth control pills

Sedatives

Other potential triggers include:

Fasting

Smoking

Drinking alcohol

Infections

Menstrual hormones

Stress

Sun exposure

Treatment of Porphyria

Outbreaks of symptoms of acute porphyria often require hospitalization. Patients may be given medicine for pain, nausea, and vomiting. They will also often receive glucose or Panhematin (hemin) injections. Panhematin is the only heme therapy approved for use in the U.S.

Severe attacks of acute porphyria can cause lasting nerve damage and muscle weakness that can take months to resolve.

Treatment of cutaneous porphyria depends on the specific type and the severity of the symptoms.

Treatment of porphyria cutanea tarda includes:

Regular blood removal (phlebotomies) to reduce the amount of iron in the liver

Low doses of the antimalarial drug chloroquine or hydroxychloroquine.

Avoidance of triggers

Diagnosis of Porphyria

Blood, urine, and stool tests are performed to diagnose porphyria. The best time to be tested is during an outbreak of symptoms or around the time of them.

Sometimes multiple tests will be required before the diagnosis of a particular type of porphyria is possible. Because porphyria often runs in families, other family members can be tested and counseled after a positive diagnosis.

**Blaschko's lines**

Blaschko's lines, also called the Lines of Blaschko, are skin lines invisible under normal conditions. They become apparent when some diseases of the skin or mucosa manifest themselves according to these patterns. They follow a "V" shape over the back, "S" shaped whorls over the chest, stomach, and sides, and wavy shapes on the head.

The lines are believed to trace the migration of embryonic cells. The stripes are a type of genetic mosaicism. They do not correspond to nervous, muscular, or lymphatic systems. The lines can be observed in other animals such as cats and dogs.

The skin lesions that follow the Blaschko's lines are varied. They include genetic, congenital and acquired (i.e. non-genetic) conditions. Examples include:

Pigmentary disorders

Naevus achromicus (including hypomelanosis of Ito)

Epidermal Naevus

Nevus sebaceous

Inflammatory linear verrucous naevus

X-linked genetic skin disorder

Incontinentia pigmenti

CHILD syndrome

Acquired inflammatory skin rashes

Lichen striatus

Lichen planus

Lupus erythematosus

Chimerism

**Mastocytosis **

Mastocytosis is a rare disorder characterized by abnormal accumulations of mast cells in skin, bone marrow, and internal organs such as the liver, spleen and lymph nodes. Cases beginning during adulthood tend to involve the inner organs in addition to the skin whereas, during childhood, the condition is often marked by skin manifestations with minimal or no organ involvement. When there is evidence of bone marrow or internal organ involvement, the disease is referred to as "systemic mastocytosis".

Although the majority of cases follow an indolent course, some patients may have evidence of a blood disorder such as a myelodysplastic or myeloproliferative disorder at the time of diagnosis. The course and prognosis of mastocytosis in these patients are determined by this associated hematologic disorder. More aggressive forms of mastocytosis and mast cell leukemias are very rarely encountered.

**Hidradenitis Suppurativa**

Hidradenitis suppurativa is a chronic, pus-producing (suppurative), scarring (cicatricial) disease process that occurs due to obstruction of hair follicles and secondary infection and inflammation of certain sweat glands (apocrine glands), particularly those under the arms (axillae) or within the anal/genital (anogenital) region. The disease is characterized by the development of recurrent, boil-like nodular lesions and deep pus-containing pockets of infection (abscesses) that may eventually rupture through the skin. Healing of affected areas is typically associated with progressive scarring (fibrosis). The specific underlying cause of hidradenitis suppurativa is unknown.

**Hallopeau-Siemens disease**

Recessive dystrophic epidermolysis bullosa (also known as "Hallopeau–Siemens variant of epidermolysis bullosa" and "Hallopeau–Siemens disease") is a skin condition resulting from mutations in the gene encoding type VII collagen, COL7A1, characterized by debilitating oral lesions that produce pain, scarring, and microstomia.

Form of epidermolysis bullosa characterized byatrophy of blistered areas, severe scarring, and nail changes. It is most often present at birth or in early infancy and occurs in both autosomal dominant and recessive forms.

**Fibrous dysplasia (FD)**

Fibrous dysplasia is a term that refers to either a group of chronic conditions featuring cystic bone growth that may arise from abnormal bone development or to a disease of bone marrow (medullary bone) characterized by benign cysts. Fibrous dysplasia is characterized by uneven growth, pain, brittleness, and deformity of the affected bones. This disorder may involve a single bone (monostotic fibrous dysplasia or Jaffe-Lichtenstein disease) or may affect multiple bones (polyostotic fibrous dysplasia). Fibrous dysplasia is usually evident during childhood, and the bone lesions usually stop developing at puberty. These lesions may be painful, deforming and widespread. The bones most often affected are the ribs, skull, facial bones, thigh bone (femur), shin bone (tibia), upper arm (humerous), and pelvis. Occasionally, the bones in the spine (vertebrae) are affected. Some, but not all, affected individuals experience repeated bone fractures. The exact cause of fibrous dysplasia is not known.

**Congenital Pulmonary ****Lymphangiectasia (Pulmonary L****ymphangiomatosis)**

Congenital pulmonary lymphangiectasia (PL) is a rare developmental disorder involving the lung and characterized by pulmonary subpleural, interlobar, perivascular, and peribronchial lymphatic dilatation. The prevalence is unknown. PL presents at birth with severe respiratory distress, tachypnea and cyanosis, with a very high mortality rate at or within a few hours of birth. Most reported cases are sporadic and the etiology is not completely understood. It has been suggested that PL lymphatic channels of the fetal lung do not undergo the normal regression process at 20 weeks of gestation. Secondary PL may be caused by a cardiac lesion. The diagnostic approach includes obtaining a complete family and obstetric history, conventional radiologic studies, ultrasound and magnetic resonance studies, lymphoscintigraphy, lung functionality tests, lung biopsy, bronchoscopy, and pleural effusion examination. During the prenatal period, all causes leading to hydrops fetalis should be considered in the diagnosis of PL. Fetal ultrasound evaluation plays a key role in the antenatal diagnosis of PL. At birth, mechanical ventilation and pleural drainage are nearly always necessary to obtain a favorable outcome of respiratory distress. Home supplemental oxygen therapy and symptomatic treatment of recurrent cough and wheeze are often necessary during childhood, sometimes associated with prolonged pleural drainage. Recent advances in intensive neonatal care have changed the previously nearly fatal outcome of PL at birth. Patients affected by PL who survive infancy, present medical problems which are characteristic of chronic lung disease.

**Gorham's disease**

Gorham's disease (GD) is an extremely rare bone disorder; fewer than 200 cases are reported in the medical literature. It is characterized by bone loss (osteolysis) often associated with swelling or abnormal blood vessel growth (angiomatous proliferation). Bone loss can occur in just one bone or spread to soft tissue and adjacent bones.

Although the disease may strike any of the bones of the body, it is more often recognized earlier when the bones at the top of the head (calvarium) and/or the mandibles are involved.

Because of its rarity, the disorder often goes unrecognized. As a result of that, coupled with a lack of agreement on how best to treat Gorham's disease once it is recognized, treatment may often be delayed. The cause of Gorham's disease is unknown.

**Melorheostosis **

Melorheostosis is a rare and progressive disease characterized by thickening (hyperostosis) of the outer layers of bone (cortical bone). Melorheostosis affects both bone and soft tissue growth and development. While the disorder is benign, it often results in severe functional limitation; extensive pain; malformed or immobilized muscles, tendons or ligaments; and limb, hand or foot deformity.

**Multiple Osteochondromas (MO)**

Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones. The prevalence is estimated at 1:50,000, and seems to be higher in males (male-to-female ratio 1.5:1). Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Osteochondromas may cause pain, functional problems and deformities (especially of the forearm), which may provide reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5% of cases. MO is an autosomal dominant disorder and is genetically heterogeneous. Germline mutations in the tumour suppressor genes, _EXT1_ or_EXT2_, are found in almost 90% of MO patients. The _EXT_ genes encode glycosyltransferases, catalyzing heparan sulphate polymerization. The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of the osteochondromas. MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease (see these terms). Osteochondromas are benign lesions and do not affect life expectancy. If the exact mutation is known antenatal diagnosis is technically possible. Management includes removal of osteochondromas when they are the cause of complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, _en-bloc_ resection of the lesion and its pseudocapsule with tumour-free margins should be performed, preferably in a bone tumour referral centre.

**Osteogenesis Imperfecta (OI)**

Osteogenesis Imperfecta (OI) is a group of rare disorders affecting the connective tissue and characterized by extremely fragile bones that break or fracture easily (brittle bones), often without apparent cause. The specific symptoms and physical findings associated with OI vary greatly from case to case. The severity of OI also varies greatly, even among individuals of the same family. OI may be a mild disorder or may result in severe complications. Four main types of OI have been identified. OI type I is the most common and the mildest form of the disorder. OI type II is the most severe. In most cases, the various forms of osteogenesis imperfecta are inherited as autosomal dominant traits.

Other definition:

Osteogenesis imperfecta (OI) comprises a heterogeneous group of genetic disorders characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity. Prevalence is estimated at between 1/10,000 and 1/20,000. Age at diagnosis depends on the severity of the disease. Five clinically distinct types of OI have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Osteogenesis imperfecta type II is lethal, type III is severe, types IV and V are moderate, and type I is mild (see these terms). Type I is nondeforming with normal height or mild short stature, blue sclera, and no dentinogenesis imperfecta (DI; see this term). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. The main signs of type III include very short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Patients with type IV have moderately short stature, mild to moderate scoliosis, grayish or white sclera, and DI. Type V is characterized by mild to moderate short stature, dislocation of the radial head, mineralized interosseous membranes, hyperplastic callus, white sclera, and no DI. Other genetically different types have been observed (types VI to IX) but they are not clinically different from types II-IV. In 95% of cases, OI is caused by mutations in the_COL1A1_ and _COL1A2_ genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1 collagen. These mutations can cause all five clinical types of OI. Transmission is autosomal dominant. Autosomal recessive forms of OI are also observed and are caused by mutations in the _LEPRE1_, _CRTAP_, and _PPIB_genes (1p34.1, 3p22 and 15q21-q22). Autosomal recessive forms are always severe forms with severe hypotonia. Diagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of wormian-like bones. Bone densitometry confirms the low bone mass. Differential diagnoses include _in utero_ diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia (see these terms), non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia. The presence of several fractures should not lead to the assumption of child abuse. Antenatal diagnosis may be suspected through ultrasonography and/or confirmed through molecular analysis of amniocytes or chorionic villus cells if the causative mutation in the family has been identified. Management should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (centro-medullary osteosynthesis). Early physiotherapy improves autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity. Functional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities.

**Paget's disease (****Osteitis Deformans)**

Paget's disease of bone is a chronic, slowly progressive skeletal condition of abnormally rapid bone destruction (osteolytic) and reformation (osteoblastic). The new bone may occur in one or more regions of the body and is structurally abnormal, dense and fragile. This abnormal development may cause bone pain, arthritis, deformities and fractures. The bones most frequently affected are in the spine, skull, pelvis and lower legs. The exact cause of Paget's disease is not known.

**Neonatal Severe Primary hyperparathyroidism (NSHPT)**

Neonatal severe primary hyperparathyroidism (NSHPT) is characterised by severe hypercalcemia ( 3.5 mM), associated with major hyperparathyroidism. Prevalence is unknown. The clinical manifestations are early (onset occurring during the first year of life) and severe, including respiratory distress, hypotonia, rib cage deformities, bone undermineralization, and multiple fractures, all of which influence the immediate vital prognosis. Biologically, the children present with extremely high levels of serum parathyroid hormone and a relative hypocalciuria. Neonatal severe hyperparathyroidism is associated in most cases with homozygous inhibiting mutations in the _CASR_ gene, localized to 3q13.3-q21. This gene encodes the calcium-sensing receptor (CaSR), a member of the subfamily of G protein-coupled transmembrane receptors. CaSR plays a key role in the regulation of phosphocalcic metabolism by controlling PTH secretion and calcium urinary excretion in response to variations in serum calcium levels. Thus, NSHPT represents the homozygous form of familial hypocalciuric hypercalcemia and is transmitted as an autosomal recessive trait. However, sporadic forms of NSHPT occur and are associated with a heterozygous _de novo_ mutation in the_CASR_ gene. The control of hypercalcemia is often obtained through progressive therapeutical intervention involving the use of biphosphonates and dialysis, before total parathyroidectomy is required.

**Fibrodysplasia ossificans progressiva**

Fibrodysplasia ossificans progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. Specifically, this disorder causes the body's skeletal muscles and soft connective tissues to undergo a metamorphosis, essentially a transformation into bone, progressively locking joints in place and making movement difficult or impossible. FOP is characterized by malformed big toes that are present at birth (congenital). Other skeletal malformations of the cervical spine and ribs and the abnormal development of bone at multiple soft tissue sites may lead episodically to stiffness in affected areas, limited movement, and eventual ankylosis of affected joints (neck, shoulders, elbows, hips knees, wrists, ankles, jaw, often in that order).

Episodic flare-ups (pre-osseous soft tissue swellings) of FOP usually begin during early childhood and progress throughout life. Most cases of FOP occur as the result of a sporadic new mutation. The genetic mutation that results in this disorder has been identified. FOP is caused by the mutation of a gene in the bone morphogenetic protein (BMP) pathway, which is important during the formation of the skeleton in the embryo and the repair of the skeleton following birth.

**Gorham-Stout Disease (Osteolysis, Essential)**

Gorham-Stout disease (GSD) is defined as a spontaneous, massive osteolysis characterized by local proliferation of small vascular or lymphatic vessels resulting in progressive destruction and resorption of bone. It is a rare condition of unknown etiology that occurs sporadically and usually affects children and young adults without sex preference. Fewer than 200 cases are reported in the literature. Since its first description in 1955, there is still controversy about its etiology, prognosis and treatment. GSD may affect one or more, often contiguous bones, with predominant sites of manifestation including the pelvis, shoulder girdle, spine, ribs and skull. Clinical signs at presentation include pain, swelling and spontaneous fractures. Osteolysis may stop progressing at any time, but often osseous tissue completely disappears, leaving only a residual fibrous band, a dramatic development inspiring the term 'vanishing bone disease.' Diagnosis is based on clinical, radiological and histopathological findings. Since GSD is usually a diagnosis of exclusion, it is important to be differentiated from osteolysis caused by infection, inflammation, endocrine disorders and tumours. No effective treatment is standardized yet. Management of GSD includes surgery, radiotherapy and various medications (alone or combined): vitamin D, sodium fluoride, calcium glycerophosphate, Interpheron alfa 2b, bisphosphonates.

**Osteochondritis**

#1. Familial osteochondritis dissecans is a rare genetic skeletal disorder characterized clinically by abnormal chondro-skeletal development, disproportionate short stature and skeletal deformation mainly affecting the knees, hips, ankles and elbows with onset generally in late childhood or adolescence.

#2. Kienbock disease is a rare bone disorder of unknown etiology characterized clinically by osteonecrosis of the carpal lunate, eventually leading to collapse of the lunate bone impacting wrist function.

#3. Legg-Calve-Perthes disease (LCPD) is the term used to describe uni- or bilateral avascular necrosis (AVN) of the femoral head in children. Reported annual incidences vary greatly, from 1/250,000 in Hong Kong and 1/18,000 in the UK, to 1/3,500 in the Faroe Islands. LCPD affects children between 2 and 12 years of age, but it is more prevalent among children of 5-6 years, and more common in boys. The initial symptoms are usually a limping gait, pain in the hip, thigh or knee, and a reduced range of hip motion. Later in the disease course, leg length discrepancy, as well as atrophy of musculature around the hip can be observed. The active phase of the disease can last for several years, and during this phase the femoral head becomes partially or completely necrotic and gradually deformed. This is followed by new bone formation (re-ossification) in the epiphysis and eventual healing. The final deformity can vary from a nearly normal joint configuration to an extensive deformation with severe flattening and subluxation of the femoral head, broadening of the femoral neck, and a deformed and dysplastic acetabulum, which in turn can lead to early-onset osteoarthritis. The etiology of LCPD remains obscure. It is generally accepted that one or more infarctions of the femoral head due to interruption of vascular supply eventually cause the deformity, however, there are several theories concerning the cause of this interruption. Several contributory factors have also been suggested: delayed skeletal maturity, impaired and disproportionate growth, short stature, low birth weight, social and economic deprivation and trauma, as well as an association with congenital anomalies. It has also been proposed that coagulation system disorders could cause thrombophilia and/or hypofibrinolysis and lead to thrombotic venous occlusion with subsequent AVN of the femoral head in children. Mutations in the _COL2A1_ gene (12q12-q13.2) have recently been identified in familial cases of AVN of the femoral head (see this term) and LCPD. Diagnosis is made by conventional radiography in frontal and lateral projections. Scintigraphy and ultrasound can be of value in selected cases and MRI can be useful in the early stages of the disease to distinguish LCPD from other hip disorders. Differential diagnoses include Meyers dysplasia, multiple epiphyseal dysplasia and spondyloepiphyseal dysplasia (see these terms). The main aim of treatment is to contain the femoral head within the acetabulum, either using an abduction brace or through surgical interventions (femoral or pelvic osteotomy). A recent study suggested that femoral osteotomy gives significantly better results than treatment with braces (specifically the Scottish Rite abduction orthosis). Prognosis is variable and several factors are of prognostic importance, such as the extent of femoral head necrosis and residual deformity. The more deformed the femoral head is during healing, the greater the risk of osteoarthritis later in life. Total hip replacement in early adulthood may be required in some cases. A younger age at diagnosis is generally accepted to be associated with a better outcome.

#4. Osgood-Schlatter disease is a traction apophysitis of the anterior tibial tubercle described in active adolescents and characterized by gradual onset of pain and swelling of the anterior knee causing limping that usually disappears at the end of growth.

#5. Osteochondritis of tarsal/metatarsal bone is a very rare form of osteochondritis dissecans characterized by generally self-limiting bone lesions that may cause pain and swelling often localized at the tarsal navicular bone

#6. Thiemann disease is a very rare genetic necrotic bone disorder characterized clinically by painless swelling of the proximal interphalangeal joints associated with osteonecrosis of epiphyses followed by osteoarthritic changes, with onset before 25 years of age and often a benign course.

**Klippel-Feil Syndrome**

Klippel-Feil syndrome (KFS) is a rare skeletal disorder primarily characterized by abnormal union or fusion of two or more bones of the spinal column (vertebrae) within the neck (cervical vertebrae). Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later during life when symptoms worsen or first become apparent.

In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include abnormal curvature of the spine (scoliosis) and/or vertebral instability, spina bifida occulta, raised scapula (Sprengel's deformity), absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart(congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury.

KFS may occur as an isolated abnormality or in association with certain syndromes. In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited as an autosomal dominant or autosomal recessive trait. Researchers have determined that some cases of KFS are associated with mutations of the GDF6 gene on chromosome 8.

**Langer-Giedion Syndrome**

#1. Trichorhinophalangeal syndrome type II (TRPS2), also known as Langer-Giedion syndrome, is an extremely rare inherited multisystem disorder. TRPS2 is characterized by fine, thin hair; unusual facial features; progressive growth retardation resulting in short stature (dwarfism); abnormally short fingers and toes (brachydactyly); "cone-shaped" formation of the "growing ends" of certain bones (epiphyseal coning); and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. In addition, affected individuals may exhibit unusually flexible (hyperextensible) joints, diminished muscle tone (hypotonia), excess folds of skin (redundant skin), and/or discolored elevated spots on the skin (maculopapular nevi). Affected individuals may also exhibit mild to severe mental retardation, hearing loss (sensorineural deafness), and/or delayed speech development. The range and severity of symptoms varies greatly from case to case. TRPS2 is due to the absence of genetic material (chromosomal deletions) on chromosome 8. The size of the deletion varies from case to case.

#2. Langer-Giedon syndrome or trichorhinophalangeal syndrome type 2 is characterized by the association of intellectual deficit and numerous other anomalies including redundant skin, multiple cartilaginous exostoses, characteristic facies and cone-shaped phalangeal epiphyses. The severity and number of these malformations varies between patients. The characteristic facial anomalies consist of a bulbous nose, wide prominent philtrum, thin upper lips, cauliflower ears, sparse hair and a small mandible. Growth retardation, microcephaly, hypotonia and hearing problems have also been reported. The exostosis affects mainly the extremities of the long bones and may lead to pain, functional problems or bone deformation. Exostoses and cone-shaped phalangeal epiphyses appear during the first 5 years of life, during which respiratory infections are frequent. The prevalence is unknown. The syndrome is transmitted in an autosomal dominant manner, but many sporadic cases have been reported. The disease is caused by a microdeletion in chromosome 8q23.3-q24.13 leading to the loss of at least two genes: _TRPS1_ and _EXT1_. Langer-Giedon syndrome can be differentiated from trichorhinophalangeal syndrome type 1 by the presence of the exostoses. Early diagnosis of Langer-Giedon syndrome is essential in order to provide genetic counselling to affected families, and to assure orthopaedic follow-up and management of the growth and hearing problems.

**Ollier ****Disease**** (Enchondromatosis)**

Ollier disease is a rare skeletal disorder characterized by abnormal bone development (skeletal dysplasia). While this disorder may be present at birth (congenital); it may not become apparent until early childhood when symptoms, such as deformities or improper limb growth, are more obvious. Ollier disease primarily affects the long bones and cartilage of the joints of the arms and legs, specifically the area where the shaft and head of a long bone meet (metaphyses). The pelvis is often involved; and even more rarely, the ribs, breast bone (sternum), and/or skull may also be affected.

Ollier disease manifests as greater than normal growth of the cartilage in the long bones of the legs and arms so that growth is abnormal and the outer layer (cortical bone) of the bone becomes thin and more fragile. These masses of cartilage are benign (non-cancerous) tumors known as enchondromas. Enchondromas may occur at anytime. After puberty these growths stabilize as cartilage is replaced by bone. In rare cases, the enchondromas may undergo malignant changes (e.g., chondrosarcomas). The exact cause of Ollier disease is not known, although in some cases it may be inherited as an autosomal dominant genetic trait.

When the enchondromas of Ollier Disease are accompanied by substantial, most often benign, proliferation of blood vessels (hemangiomas), the array of symptoms is known as Maffucci Syndrome.

**Tietze's Syndrome**

Tietze syndrome is a rare, inflammatory disorder characterized by chest pain and swelling of the cartilage of one or more of the upper ribs (costochondral junction). Onset of pain may be gradual or sudden and may spread to affect the arms and/or shoulders. Tietze syndrome is considered a benign syndrome and, in some cases, may resolve itself without treatment. The exact cause of Tietze syndrome is not known.

**Acrocephalosyndactylia (Apert Syndrome)**

Apert syndrome is a genetic disorder characterized by the premature fusion of certain skull bones (craniosynostosis). This early fusion prevents the skull from growing normally and affects the shape of the head and face. In addition, a varied number of fingers and toes are fused together (syndactyly).

Many of the characteristic facial features of Apert syndrome result from the premature fusion of the skull bones. The head is unable to grow normally, which leads to a sunken appearance in the middle of the face, bulging and wide-set eyes, a beaked nose, and an underdeveloped upper jaw leading to crowded teeth and other dental problems. Shallow eye sockets can cause vision problems. Early fusion of the skull bones also affects the development of the brain, which can disrupt intellectual development. Cognitive abilities in people with Apert syndrome range from normal to mild or moderate intellectual disability.

Individuals with Apert syndrome have webbed or fused fingers and toes. The severity of the fusion varies; at a minimum, three digits on each hand and foot are fused together. In the most severe cases, all of the fingers and toes are fused. Less commonly, people with this condition may have extra fingers or toes (polydactyly). Additional signs and symptoms of Apert syndrome can include hearing loss, unusually heavy sweating (hyperhidrosis), oily skin with severe acne, patches of missing hair in the eyebrows, fusion of spinal bones in the neck (cervical vertebrae), and recurrent ear infections that may be associated with an opening in the roof of the mouth (a cleft palate). Apert syndrome affects an estimated 1 in 65,000 to 88,000 newborns.

Mutations in the _FGFR2_ gene cause Apert syndrome. This gene produces a protein called fibroblast growth factor receptor 2. Among its multiple functions, this protein signals immature cells to become bone cells during embryonic development. A mutation in a specific part of the _FGFR2_ gene alters the protein and causes prolonged signaling, which can promote the premature fusion of bones in the skull, hands, and feet.

Apert syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Almost all cases of Apert syndrome result from new mutations in the gene, and occur in people with no history of the disorder in their family. Individuals with Apert syndrome, however, can pass along the condition to the next generation.

**Acrodermatitis**

Acrodermatitis enteropathica (AE) is a disorder of zinc metabolism that occurs in one of two forms: an inborn (congenital) form and an acquired form. The inborn form of AE is a rare genetic disorder characterized by intestinal abnormalities that lead to the inability to absorb zinc from the intestine. The lack of zinc presents, characteristically, as: (1) skin inflammation with pimples (pustular dermatitis) occurring around the mouth and/or anus, (2) diarrhea, and (3) abnormal nails (nail dystrophy). In the acute phase, irritability and emotional disturbances are evident due to wasting (atrophy) of the brain cortex. It is important to recognize and treat this disorder.

The acquired form of this disorder generates similar symptoms. Acquired AE sometimes results from special intravenous nutritional programs that are prepared without the appropriate amount of zinc.

**Addison****Disease**

Addison's disease is a rare disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the outer layer of cells of the adrenal glands (adrenal cortex). The symptoms of classic Addison's disease, also known as primary adrenal insufficiency, result from the insufficient production of these two hormones. Major symptoms include fatigue, gastrointestinal abnormalities, and changes in skin color (pigmentation). Behavior and mood changes may also occur in some individuals with Addison's disease. Increased excretion of water and low blood pressure (hypotension) can lead to extremely low concentrations of water in the body (dehydration). The symptoms of Addison's usually develop slowly, but sometimes can develop rapidly, a serious condition called acute adrenal failure. In most cases, Addison's disease occurs when the body's immune system mistakenly attacks the adrenal glands causing slowly progressive damage to the adrenal cortex.

**Adie Syndrome**

Adie Syndrome is a rare neurological disorder affecting the pupil of the eye. In most patients the pupil is dilated (larger than normal) and slow to react to light on nearby objects. In some patients, however, the pupil may be constricted (smaller than normal) rather than dilated. Absent or poor reflexes are also associated with this disorder. Adie Syndrome is neither progressive nor life threatening, nor is it disabling.

**Alagille Syndrome**

Alagille syndrome is a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. The specific symptoms and severity of Alagille syndrome can vary greatly from one person to another, even within the same family. Some individuals may have mild forms of the disorder while other may have more serious forms. Common symptoms, which often develop during the first three months of life, include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth, severe itching (pruritis) and pale, loose stools. Additional symptoms include heart murmurs, congenital heart defects, vertebral (back bone) differences, thickening of the ring that normally lines the cornea in the eye (posterior embryotoxon) and distinctive facial features. Most cases of Alagille syndrome occur due to mutations in one copy of the JAG1 gene. A small percentage (less than 1 percent) of cases occur due to mutations of the NOTCH2 gene. These mutations are inherited as autosomal dominant traits.

**Amyotrophic Lateral Sclerosis**

Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) sent messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig's disease.

**Angelman Syndrome**

Angelman syndrome (AS) is a rare genetic neurological disorder characterized by severe developmental delays and learning disabilities; the absence or near absence of speech; an inability to coordinate voluntary movements (ataxia) and tremulous, jerky movements of the arms and legs; and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling, often at inappropriate times. Although affected individuals may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand language to understand simple commands. Additional symptoms may occur in some cases including seizures, sleep disorders and feeding difficulties. Some affected children may have distinctive facial features.

Angelman syndrome is caused by deletion of or abnormal expression of the UBE3A gene that is located on the long arm (q) of chromosome 15 (15q11-q13). In most affected individuals, Angelman syndrome appears to occur spontaneously (sporadically) for unknown reasons. However, some familial cases have been reported.

**Angina****Pectoris, Variant**

Variant angina is an extremely rare form of angina pectoris that is caused by a spasm in a coronary artery. While other types of angina generally occur in people with coronary artery disease, variant angina may occur in those with or without the condition. The primary symptom is severe pain in or around the chest, shoulders, jaw, neck, back, or arms.

Angina pectoris, or angina for short, is chest pain or discomfort that occurs when the heart muscle is not getting enough oxygen-rich blood for a short period of time.

In order to understand angina, it is often helpful to understand the heart and the coronary arteries. Like any muscle, the heart needs a constant supply of oxygen and nutrients, which are carried to it by the blood in the coronary arteries. Similar to other muscles, the harder the heart is working, the more oxygen and nutrients it needs.

However, the coronary arteries can become narrowed or clogged, which can decrease the amount of blood that goes to the heart muscle. When the coronary arteries cannot supply enough oxygen-rich blood to the heart, angina symptoms can occur.

Variant angina is caused by a spasm in a coronary artery. This spasm causes the walls of the artery to tighten. This narrows the artery, causing the blood flow to the heart to slow or stop.

Unlike other types of anginathat usually occur in someone with coronary artery disease (also called CAD or just heart disease), variant angina may occur in people with or without this condition.

Severe chest pain is the main symptom of variant angina. People with symptoms of the condition usually feel a pressure-like pain in or around the:

Chest

Shoulders

Jaw

Neck

Back

Arms.

It may feel like a squeezing, pressing sensation in the chest.

Other symptoms of variant angina can include:

Indigestion or heartburn-type sensation

Nausea

Fatigue

Shortness of breath

Sweating

Lightheadedness

Weakness.

The severe pain or discomfort associated with variant angina:

Usually occurs at rest

Occurs between midnight and early morning hours

Is relieved by angina medicine.

Stable angina, also known as exertional angina, is the most common form. In people with this condition, the coronary arteries are narrowed due to a buildup of plaque. During physical activity, the narrowed arteries have a difficult time getting enough oxygen, which, in turn, causes symptoms such as chest pain. However, with rest and/or medication, the condition generally improves.

More than 6 million Americans live with angina pectoris, or angina for short. Angina is chest pain or discomfort that occurs when the heart muscle is temporarily not getting enough oxygen-rich blood. A bout of angina is not a heart attack, but it means that you're more likely to have a heart attack than someone who doesn't have angina.

In order to understand the cause of stable angina, it is often helpful to understand the heart and the coronary arteries. Like any muscle, the heart needs a constant supply of oxygen and nutrients, which are carried to it by the blood in the coronary arteries. Similar to other muscles, the harder the heart is working, the more oxygen and nutrients it needs. However, the coronary arteries can become narrowed or clogged, which can decrease the amount of blood that goes to the heart muscle. When the coronary arteries cannot supply enough oxygen-rich blood to the heart, angina symptoms can occur.

Angina pectoris, or angina for short, is caused by a temporary lack of oxygen-rich blood to the heart muscle. This decrease in blood flow can happen for a number of reasons, and will vary based on the type of angina. The most common cause of angina is coronary artery disease (CAD), or what most people refer to as just heart disease. Sometimes, other types of heart disease(such as aortic stenosis) or uncontrolled high blood pressure can cause this condition. There are also a number of factors that can trigger an angina attack.

In order to understand angina causes, it is often helpful to understand the heart and the coronary arteries. Like any muscle, the heart needs a constant supply of oxygen and nutrients, which are carried to it by the blood in the coronary arteries. Similar to other muscles, the harder the heart is working, the more oxygen and nutrients it needs. However, the coronary arteries can become narrowed or clogged, which can decrease the amount of blood that goes to the heart muscle. When the coronary arteries cannot supply enough oxygen-rich blood to the heart, angina symptoms can occur.

For most people with stable angina, symptoms are brought on by certain factors, known as triggers. Specific triggers can include:

Physical exertion, such as exercise, hurrying, or sexual activity

Emotion (stress, anger, frustration, or fright)

Exposure to very hot or cold temperatures

Heavy meals

Smoking.

**Angiolymphoid Hyperplasia with Eosinophilia**

Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon idiopathic condition that manifests in adults as isolated or grouped papules, plaques, or nodules in the skin of the head and neck. Most patients present with lesions in the periauricular region,[1] forehead, or scalp. Rare sites of involvement include the hands,[2] shoulders, breasts, penis, oral mucosa, orbit, and, recently, a report involving the scrotum.[3]

A distinct pathologic entity, ALHE is marked by a proliferation of blood vessels with distinctive large endothelial cells. These blood vessels are accompanied by a characteristic inflammatory infiltrate that includes eosinophils. The lesion is benign but may be persistent and is difficult to eradicate.

While ALHE shows some similarity to Kimura disease, it is generally regarded as a separate entity.[4, 5] While ALHE lesions are superficial, Kimura disease involves deeper tissues such as lymph nodes, salivary glands, and the subcutis. However, a 2006 report describes ALHE involving the nail bed and underlying bone.[6] Only one report describes a patient with simultaneous tumors, one consistent with Kimura disease and one consistent with ALHE.[7] Such findings challenge whether or not Kimura disease and ALHE represent a spectrum of the same disease.

Angiolymphoid hyperplasia with eosinophilia (ALHE) typically appears as dome-shaped, smooth-surfaced papules or nodules (see the image below). Approximately 85% of lesions occur in the skin of the head and neck; most of them are on or near the ear or on the forehead or scalp. The extremities are the next most common site. Involvement at other sites is rare. However, case reports have described ALHE affecting the penis[18] and the conjunctiva.[19]

The lesions range from erythematous to brown, and they may be eroded or crusted. Approximately 80% of patients present with isolated lesions, while the remaining patients usually demonstrate grouped papules or nodules in a single region. Rarely, the lesions may be pulsatile. Most lesions are 0.5-2 cm in diameter, with a range of 0.2-8 cm. Larger nodules tend to be deeply centered within the subcutis.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is idiopathic. Whether this condition is a neoplastic or reactive state is uncertain; a reactive cause is favored.

**Arnold-Chiari Malformation**

Arnold-Chiari Malformation (Type 1) is a rare malformation where the base of the brain enters into the upper spinal canal.

The symptoms of Arnold-Chiari Malformation include:

Upper motor neurone and cerebellar signs

Clumsiness

Awkward

"drunken" like gait/walking difficulties

Bilateral problems with co-ordination of movement

Disjointed speech

Headache

Vomiting

Vertigo

Nystagmus (uncontrolled horizontal or vertical movement of eyes)

Asymptomatic

Recurrent headache

Neck pain

Pins and needles sensation

Urinary frequency

Progressive lower limb spasticity

Swelling of optic disk

Rapid involuntary eye movements

Posterior column nerve palsy

Lateral column nerve palsy

Cerebellar ataxia

Narrow foramen magnum

Herniation of cerebral tonsils

Increased spinal fluid pressure

Increased spinal fluid proteins

**Arthritis, Juvenile Rheumatoid**

Arthritis, systemic-onset juvenile rheumatoidis a form of joint disease in children whose systemic signs and symptoms include high intermittent fever, a salmon-colored skin rash, swollen lymph glands, enlargement of the liver and spleen, inflammation of the lungs (pleuritis), and inflammation around the heart (pericarditis). The arthritis itself may not be immediately apparent, but in time it surfaces and may persist after the systemic symptoms are long gone. Also known as systemic-onset chronic arthritis or Still's disease.

There are three main forms of juvenile rheumatoid arthritis (JRA), which are classified by how they begin. These forms are pauciarticular (less than four joints affected), polyarticular (four or more joints affected), and systemic-onset (inflamed joints with high fevers and rash). Pauciarticular juvenile rheumatoid arthritis (JRA) is defined by the involvement of less than four joints after six months of illness. This form often begins in young girls as a swollen knee or ankle that appears without injury or explanation. Usually it is "painless," but someone may notice that the knee looks swollen or the child is walking awkwardly. Since arthritis causes morning stiffness, parents are slow to get concerned about this because "she always looks okay once she gets going." This arthritis is often very mild and treated just with mild nonsteroidal antiinflammatory drugs, but it can cause two important problems. A serious problem that many children with pauciarticular juvenile rheumatoid arthritis (JRA) develop is inflammation of the eye (iridocyclitis). The inflammation is not painful, but if not detected and treated, it may lead to scarring of the lens and permanent visual damage (even blindness). At the beginning, this inflammation cannot be seen except by an ophthalmologist using a special instrument called a "slit lamp." Because the eye disease is more common in children with a positive test for antinuclear antibodies (ANA), these children require eye examinations every three months by an eye specialist. All other children with juvenile rheumatoid arthritis (JRA) need eye examinations every six months. No one has been able to completely explain the association of eye disease and arthritis or why it is more frequent in children with ANA. But we do know it happens, and it's important to make sure every child's eyes get checked.

The second important problem with pauciarticular juvenile rheumatoid arthritis (JRA) is that it may cause the bones in the legs to grow at different rates with the result that one leg is longer than the other. When this happens, children are forced to walk with a limp. This damages the knee and the hip leading to premature arthritis, from "wearing out" the joints by the time the child is an adult, and should be prevented. Fortunately, this can be recognized early. When the knee or another joint is inflamed by the arthritis, its blood supply increases. Then, just like a plant that receives more water than the plants around it, it grows faster and larger. Doctors are always trying to stop the inflammation to prevent this problem. Most often the therapy is successful and the child does not develop a significant leg-length discrepancy. If he or she does, we can do two things. First we can put a lift in the shoe on the short side to correct the effect of the different leg lengths. This doesn't do anything for the knee, but it prevents excessive wear on the hip and allows the child to walk more normally. The next step is to monitor growth. When the child is getting closer to fully grown, an orthopedist can look at x-rays of the legs and try to guess when the bones are going to stop growing. If the leg with arthritis is 3 cm longer than the other leg, they will look at the x-rays and try to guess when there is 3 cm of leg growth left. Then you stop the growth on the leg that is too long and allow the short leg to catch up. This can be done with a very simple operation.

Polyarticular juvenile rheumatoid arthritis is the form in which four or more joints are involved after six months of illness. This form is more severe both because of the greater number of joints involved and the fact that it tends to get worse over time. These children may have a great deal of difficulty with normal activities and need to be treated aggressively.

From a doctor's point of view, the most important thing is to bring inflammatory arthritis under control as quickly as possible. Typically, this involves at least medications that reduce inflammation, nonsteroidal antiinflammatory drugs (NSAIDs). This may also require use of some fairly strong medications, but it's important to recognize that they are necessary to reduce symptoms and prevent permanent damage. One thing to watch out for is using steroids (for example, prednisone). In severe cases, this may be necessary, but it is not a "real" solution. Steroids make patients with arthritis feel wonderful, but it's like sweeping dirt under the rug. Everything looks good, but it really isn't. Taking too much steroid for a long period causes lots of problems, like short stature and weak bones. Whenever we are required to put a child on steroid medications, we want to wean them as quickly as possible. Nonsteroidal antiinflammatory drugs are enough for many children with polyarticular juvenile rheumatoid arthritis, but more severe cases may require more aggressive "second-line" medications, such as gold shots, sulfasalazine, or methotrexate. Severe cases requiring steroids or second-line medications should be under the care of experienced physicians.

A newer form of medication, biologics called TNF-blockers, is now available. Tumor necrosis factor alpha (TNF-alpha) is a substance made by cells of the body that has an important role in promoting inflammation. By blocking the action of TNF-alpha, TNF-blockers reduce the signs and symptoms of inflammation. Etanercept (Enbrel) is a self-injectable TNF-blocker that is injected into the skin twice weekly and is indicated for reduction in signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying medicine(s). Infliximab (Remicade) is an intravenously infused antibody that blocks the effects of TNF-alpha. Remicade is given by intravenous infusion every two months. Remicade is effective for treating juvenile rheumatoid arthritis and can result in a significant and prompt reduction in disease activity and improved quality of life. Adalimumab (Humira) is also a self-injectable TNF-blocker that reduces the signs and symptoms of moderate to severely active polyarticular juvenile inflammatory arthritis in children 4 years of age or older.

Often the most difficult form of juvenile rheumatoid arthritis is systemic-onset JRA, also known as Still's disease. This form of juvenile rheumatoid arthritis begins with high fevers and a rash. It is very important in this setting to make sure the patient really has systemic-onset juvenile rheumatoid arthritis and not another condition, such as infection. One of the most important findings is that the fever goes away for at least part of every day in someone with systemic-onset juvenile rheumatoid arthritis. Usually the fever is high once or twice each day. At those times, the child looks very sick and doesn't want to be touched, but when the fever goes down to normal again, they look and feel better. Sometimes it goes completely away and never comes back again. Other times, the fevers and rash go away, but the arthritis progresses over time and can be very severe. This form of juvenile rheumatoid arthritis can involve the internal organs and rarely is a "life-threatening" disease.

Treatments for systemic-onset JRA include nonsteroidal antiinflammatory drugs (NSAIDs such as ibuprofen and naproxen), hydroxychloroquine (Plaquenil), cortisone medications (such as prednisone and prednisolone), methotrexate, and for resistant disease, anakinra (Kineret). Some research has suggested that thalidomide may be an effective treatment for children with systemic-onset JRA.

**Asperger Syndrome**

Asperger's syndrome, also known as Asperger disorder or Asperger syndrome, is one of a group of neurodevelopmental disorders that have effects on an individual's behavior, use of language and communication, and pattern of social interactions. Asperger disorder is characterized as one of the autism spectrum disorders (which also include autistic disorder, Rett disorder, childhood disintegrative disorder, and pervasive developmental disorder-not otherwise specified [PDD-NOS]), although Asperger's syndrome is considered to be at the milder, or higher-functioning, range of this spectrum. There is still some controversy as to whether Asperger's syndrome should be regarded as a separate clinical entity or simply represents a high-functioning form of autism. People with Asperger's syndrome have normal to above-average intelligence but typically have difficulties with social interactions and often have pervasive, absorbing interests in special topics.

Asperger's syndrome is named for Dr. Hans Asperger, an Austrian pediatrician, who first described the condition in 1944. Dr. Asperger described four boys who showed "a lack of empathy, little ability to form friendships, one-sided conversation, intense absorption in a special interest, and clumsy movements." Because of their obsessive interests in and knowledge of particular subjects, he termed the boys "little professors." The American Psychiatric Association (APA) recognized Asperger disorder as a specific entity and published diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) in 1994. Most recently, after significant deliberation, the APA recommended "subsuming" Asperger's Disorder into Autism Spectrum Disorders for the next edition DSM-V. However, there has been significant academic debate regarding this decision, and since this edition is not expected to be approved and published until 2013, there will be more debates on the matter.

Today, many experts in the field stress the particular gifts and positive aspects of Asperger syndrome and consider it to represent a different, but not necessarily defective, way of thinking. Positive characteristics of people with Asperger syndrome have been described as beneficial in many professions and include:

the increased ability to focus on details,

the capacity to persevere in specific interests without being swayed by others' opinions,

the ability to work independently,

the recognition of patterns that may be missed by others,

intensity

original way of thinking.

**Bardet-Biedl Syndrome**

Bardet-Biedl Syndrome is a rare genetic disorder characterized by mental retardation, obesity, polydactyly and retinal pigmentation as well as other abnormalities.

The list of signs and symptoms mentioned in various sources for Bardet-Biedl Syndrome includes the 42 symptoms listed below:

Obesity

Short stature

Mental deficiency

Low verbal I Q

Low performance I Q

Inappropriate mannerisms

Visual impairment

Retinal dystrophy

Myopia

Astigmatism

Nystagmus

Blaucoma

Posterior capsular cataracts

Mature cataracts

Aphakia

Retinitis pigmentosa

Postaxial polydactyly

Syndactyly

Brachydactyly of hands

Broad feet

Short feet

Abnormal kidney calyces

Communicating kidney cysts

Communicating kidney diverticulae

Fetal kidney lobulations

Diffuse cortical loss in kidney

Focal kidney scarring

Small penis

Small testes

Abnormal color vision

Abnormal kidney structure

Abnormal kidney function

Degeneration of retina

Hypogonadism

Delayed sexual development

Urogenital sinuses

Ectopic urethra

Septate vagina

Uterus duplex

Hypoplastic uterus

Hypoplastic ovaries

Hypoplastic fallopian tubes

**Barrett Esophagus**

Barrett's esophagus is a complication of chronic gastroesophageal reflux disease (GERD), primarily in white men. GERD is a disease in which there is reflux of acidic fluid from the stomach into the esophagus (the swallowing tube). It most commonly causes heartburn

Barrett's esophagus is officially coded by the Library of Congress for electronic searches of the literature as Barrett esophagus, but Barrett's esophagus (with the apostrophe "s") is the name used universally. The condition is named after a surgeon, Norman Barrett, who described the condition. However, it turns out that his interpretation of the findings was not correct. In 1953, Doctors' Allison and Johnstone actually described this condition as we now understand it, namely that metaplasia was occurring. (Metaplasia, which is discussed below, is the term used when one adult tissue replaces another.) Nevertheless, the condition has been immortalized with Barrett's name.

Initially, it was thought that the Barrett's esophagus consisted of stomach (gastric) tissue replacing the usual squamous tissue lining the esophagus. However, in the mid 70's, Dr. Paull and colleagues published a paper in which they described the mucosa (inner lining) of Barrett's esophagus in greater detail than had been done previously. They pointed out that Barrett's esophagus consisted of a metaplasia in which the normal cells lining the esophagus were replaced by a mixture of gastric and intestinal lining cells. The intestinal-type lining cells also are called specialized columnar cells which include goblet cells. For a number of years, some scientists thought that there were two types of Barrett's; one in which the normal lining was replaced with stomach (gastric) type cells only, and the second in which intestinal cells were present. However, the current belief is that only the presence of intestinal-type goblet cells establishes the diagnosis of Barrett's esophagus, regardless of what other cell types are present.

Barrett's esophagus has no unique symptoms. Patients with Barrett's have the symptoms of GERD (for example, heartburn, regurgitation, nausea, etc.). The general trend is for Barrett's patients to have more severe GERD. However, not all Barrett's have marked symptoms of GERD, and some patients are detected accidentally with minimal or no symptoms of GERD.

Heartburn is a burning sensation behind the breastbone, usually in the lower half, but may extend all the way up to the throat. Sometimes, it is accompanied by burning or pain in the pit of the stomach just below where the breastbone ends. The second most common symptom is regurgitation (backup) of bitter tasting fluid. GERD symptoms often are worse after meals and when lying flat.

The refluxed, regurgitated fluid occasionally may enter the lungs or the voice box (larynx), resulting in what are called extraesophageal (outside the esophagus) symptoms (manifestations) of GERD. These symptoms include:

new onset adult asthma

frequent bronchitis

chronic cough

sore throats

hoarseness.

For reasons not fully understoood, some GERD patients have minimal heartburn but experience other GERD symptoms, for example, extraesophageal symptoms.

GERD may result in strictures and ulceration of the esophagus. A stricture or narrowing is due to scarring (fibrosis) of the esophagus that may cause difficulty in swallowing (dysphagia). The dysphagia is sensed as a sticking (stopping) of solid food in the chest (in the esophagus), and liquids when the narrowing is severe. Strictures can be treated by stretching them with dilators during endoscopy. Untreated, strictures may promote more spillage of food and/or gastric fluids into the lungs. Uncommonly, massive gastrointestinal (GI) bleeding caused by inflammation of the esophagus may occur. Such bleeding results in vomiting of blood or passage of black or maroon stools. More commonly, however, an inflamed esophagus can cause slow bleeding that is detected when anemia (a low red blood cell count) is found and/or stools are tested for blood.

**Beckwith-Wiedemann Syndrome**

Beckwith-Wiedemann syndrome is an overgrowth syndrome, whose clinical manifestations typically include macrosomia (large body size), macroglossia (large tongue), omphalocele (exomphalos), organomegaly (enlarged organs), hemihypertrophy (overgrowth of one side of the body), neonatal hypoglycemia (low blood sugar in the newborn period), and ear creases and ear pits.

Patients with this syndrome have an increased risk of embryonal malignancies such as Wilms tumor, hepatoblastoma, neuroblastoma, adrenocortical cancer, and rhabdomyosarcoma.

The majority (about 85%) of patients with Beckwith-Wiedemann syndrome (BWS) have no family history of it while a minority (about 15%) of patients have a family history with autosomal dominant transmission of the syndrome.

The genetics of BWS appear complex, in part no doubt because the underlying causes of the syndrome are still not entirely clear. In 50% of patients, there is loss of methylation at the KCNQ1OT1 gene in chromosome 11p15 while in 10-20% of patients, there is paternal uniparental disomy of chromosome 11p15. There are mutations in the CDKN1C gene in chromosome 11p15 in 5-10% of cases with no known family history of the syndrome and 40% of familial cases of the syndrome.

The syndrome is named for the American pediatric pathologist J. Bruce Beckwith (1933-) and the German pediatrician Hans-Rudolf Wiedemann (1915-). In 1964, Wiedemann reported a familial form of omphalocele with macroglossia in Germany and then in 1969, Beckwith described a similar series of patients in the US. Wiedemann coined the term EMG syndrome to describe the combination of exomphalos, macroglossia, and gigantism. In time, the condition was renamed Beckwith-Wiedemann syndrome. It is also sometimes called the Wiedemann-Beckwith syndrome (WBS) because Wiedemann recognized the syndrome before Beckwith.

**Behcet Syndrome**

Behcet's syndrome is classically characterized as a triad of symptoms that include recurring crops of mouth ulcers (aphthous ulcers), genital ulcers, and inflammation of a specialized area around the pupil of the eye (the uvea). The inflammation of the area of the eye that is around the pupil is called uveitis. Behcet's syndrome is also sometimes referred to as Behcet's disease.

The cause of Behcet's syndrome is not known. The disease is more frequent and severe in patients from the Eastern Mediterranean and Asia than those of European descent. Both inherited (genetic) and environmental factors, such as microbe infections, are suspected to be factors that contribute to the development of Behcet's syndrome. Behcet's syndrome is not felt to be contagious.

The symptoms of Behcet's syndrome depend on the area of the body affected. Behcet's syndrome can involve inflammation of many areas of the body. These areas include the arteries that supply blood to the body's tissues. Behcet's syndrome can also affect the veins that take the blood back to the lungs to replenish the oxygen content. Other areas of body that can be affected by the inflammation of Behcet's syndrome include the back of the eyes (retina), brain, joints, skin, and bowels.

The mouth and genital ulcers are generally painful and recur in crops (many shallow ulcers at the same time). They range in size from a few millimeters to 20 millimeters in diameter. The mouth ulcers occur on the gums, tongue, and inner lining of the mouth. The genital ulcers occur on the scrotum and penis of males and vulva of women and can leave scars.

Inflammation of the eye, which can involve the front of the eye (uvea) causing uveitis, or the back of the eye (retina) causing retinitis, can lead to blindness. Symptoms of eye inflammation include pain, blurred vision, tearing, redness, and pain when looking at bright lights. It is very important for patients to have this sensitive area monitored by an eye specialist (ophthalmologist).

If the arteries become inflamed (arteritis) in patients with Behcet's syndrome, it can lead to death of the tissues whose oxygen supply depends on these vessels. This could cause a stroke if affecting the brain, belly pain if affecting the bowel, etc. When veins become inflamed (phlebitis), the inflammation can involve large veins that develop blood clots which can loosen to cause pulmonary embolism.

Symptoms of inflammation of the brain or tissue that covers the brain (meninges) include headaches, neck stiffness, and is often associated with fever. Inflammation of the brain (encephalitis) and/or the meninges (meningitis) can cause damage to nervous tissue and lead to weakness or impaired function of portions of the body. This can result in confusion and coma. Typically these features occur later in the disease course, years after the diagnosis.

Joint inflammation (arthritis) can lead to swelling, stiffness, warmth, pain, and tenderness of joints in patients with Behcet's syndrome. This occurs in about half of patients with Behcet's syndrome at sometime during their lives. Knees, wrists, ankles, and elbows are the most common joints affected.

The skin of patients with Behcet's syndrome can develop areas of inflammation which spontaneously appear as raised, tender, reddish nodules (erythema nodosum), typically on the front of the legs. Some patients with Behcet's syndrome develop a peculiar red or blistery skin reaction in places where they have been pierced by blood-drawing needles (see pathergy test in diagnosis section below). Recent research has found that acne occurs more frequently in patients with Behcet's syndrome that also have arthritis as a manifestation.

Ulcerations can occur at any location in the stomach, large or small bowel in patients with Behcet's disease.

**Bowen's Disease**

Bowen's disease is medically the same as "squamous cell carcinoma in situ." Squamous cell carcinoma is a tumor that develops from the squamous cells which are flat, scale-like cells in the outer layer of the skin (the epithelium). The term "in situ" (borrowed from the Romans) means "in the natural or normal place" and, in the case of cancer, it says that the tumor cells are still confined to the site where they originated and they have neither invaded neighboring tissues nor metastasized afar.

The hallmark of Bowen's disease is a persistent, progressive, slightly raised, red, scaly or crusted plaque. Bowen's disease may occur anywhere on the skin surface (or on mucosal surfaces such as in the mouth).

Under the microscope, atypical squamous cells are seen to have proliferated through the whole thickness of the epidermis (the outer layer of the skin) but to have gone no farther.

The cause of Bowen's disease classically was prolonged exposure to arsenic. Today, Bowen's disease occurs most often in the sun-exposed areas of the skin in "older" white males.

Treatment options include freezing with liquid nitrogen, cauterization (burning), surgical removal, and chemosurgery.

Bowen's disease is named after the American dermatologist John Templeton Bowen's (1857-1941).

**Brachial Plexus Neuropathies**

Brachial plexus neuropathy are diseases of the cervical (and first thoracic) roots, nerve trunks, cords, and peripheral nerve components of the branchial plexus. Clinical manifestations include regional pain, paresthesia; muscle weakness, and decreased sensation (hypesthesia) in the upper extremity. These disorders may be associated with trauma (including birth injuries); thoracic outlet syndrome; neoplasms; neuritis; radiotherapy; and other conditions. (From Adams et al., Principles of Neurology, 6th ed, pp1351-2) The brachial plexus is an anatomical network composed of five spinal nerves. Four of these exit the spinal cord through the cervical spine, which is the area below the skull and above the shoulders, while one exits through the thoracic spine, which supports the upper torso. The nerves of the brachial plexus supply nerve impulses to the shoulder, arm, hand and diaphragm. Injury to the nerves, also called neuropathy, of the brachial plexus can affect any of the structures that this nerve group supplies.

The following symptoms may occur:

Numbness

Abnormal sensation

Weakness

Horner Syndrome

**Brown-Sequard Syndrome**

Brown-Sequard syndrome (BSS) is a rare neurological condition characterized by a lesion on the spinal cord which results in weakness or paralysis (hemiparaplegia) on one side of the body and a loss of sensation (hemianesthesia) on the opposite side. It is a syndrome associated with injury to the lateral half of the spinal cord. The condition is characterized by the following clinical features (which are found below the level of the lesion): contralateral hemisensory anesthesia to pain and temperature, ipsilateral loss of propioception, and ipsilateral motor paralysis. Tactile sensation is generally spared.

The list of signs and symptoms mentioned in various sources for Brown-Sequard Syndrome includes the 12 symptoms listed below:

Hemiparaplegia

Hemianesthesia - on the opposite side to the paralysis

Paralysis of voluntary muscles below level of lesion

Segmental atrophy at level of lesion

Sensory loss at level of lesion

Contralateral analgesia below lesion

Thermanesthesia below lesion

Sphincteral disturbances

Increased muscle tone at side of lesion

Increased deep reflexes

Clonus

Babinski sign

**Burkitt Lymphoma**

Burkitt lymphoma is a type of non-Hodgkin lymphoma (NHL) that most often occurs in young people between the ages of 12 and 30, accounting for 40% to 50% of childhood NHL. The disease usually causes a rapidly growing tumor in the abdomen. Up to 90% of these tumors are in the abdomen. Other sites of involvement include the testis, sinuses, bone, lymph nodes, skin, bone marrow, and central nervous system.

Burkitt lymphoma is a small noncleaved cell lymphoma of B-cell origin. About 25% of Burkitt lymphomas contain Epstein-Barr virus genomes. Burkitt lymphoma is due to a characteristic chromosomal translocation, usually a t(8;14) translocation or, less often, a t(8;22) or t(2;8) translocation. Each of these translocations juxtaposes the c-myc oncogene with immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation.

Named for Denis Burkitt (1911-1993), a British surgeon who worked for many years in Africa. There he saw two children in rapid succession in 1957 with fast-growing, fatal tumors of the head and neck, assembled similar cases from other hospitals in Africa, and in 1958 reported what is now called Burkitt lymphoma.

**Carcinoma 256, Walker**

A transplantable carcinoma of the rat that originally appeared spontaneously in the mammary gland of a pregnant albino rat, and which now resembles a carcinoma in young transplants and a sarcoma in older transplants. It's not really a disease, but it can help with the treatment of other diseases involving carcinoma's.

**Caroli Disease**

Caroli Disease is a rare disorder where the bile ducts inside the liver become enlarged resulting in infection, irritation and gallstone formation.

The list of signs and symptoms mentioned in various sources for Caroli Disease includes the 11 symptoms listed below:

Nausea

Vomiting

Stomach pain

Fever

Enlarged liver

Liver abscesses

Kidney infection

Liver infection

Gallstones

Abdominal pain

Sepsis

**Chagas Disease**

Chagas disease (also termed American trypanosomiasis) is an infection caused by a protozoan parasite (_Trypanosoma cruzi_) that can result in acute inflammatory skin changes (chagomas) and eventually may cause infection and inflammation of many other body tissues, especially those of the heart and intestinal tract. The disease may have three phases in an individual: acute, with mild or no symptoms that may last weeks to about two months; intermediate or indeterminate phase that has few if any symptoms and may last 10-20 years or longer; and chronic phase that appears after about 20 years, with the more severe symptoms appearing from gradual chronic organ damage (especially to the heart and intestine, although other organs may be affected) with symptoms that usually remain for life. People with Chagas disease seen in the U.S. usually have acquired it while living in a country where the disease is endemic (Mexico, Central and South America). The CDC estimates about 8-11 million people are infected in countries where the disease is endemic.

The symptoms of Chagas disease can be quite variable and range from no symptoms at all to severe and distressing symptoms. The first symptoms, when present in the acute phase, may include some of the following:

Swelling and/or redness at the skin infection site (termed chagoma)

Rash

Swollen lymph nodes

Fever

Head and body aches

Fatigue

Nausea, vomiting, and/or diarrhea

Liver and/or spleen enlargement

Romaña sign (unilateral painless edema [swelling] of tissues around the eye)

Symptoms of chronic Chagas disease vary according to the organs most affected; in most cases, the heart or the gastrointestinal tract (or both) show the most serious symptoms. Chronic Chagas disease symptoms may include the following:

Irregular heartbeats

Palpitations

Fainting (syncope)

Cardiomyopathy (chronic disease of the heart muscle)

Congestive heart failure

Shortness of breath (dyspnea)

Emphysema

Stroke

Sudden death

Chronic abdominal pain

Chronic constipation

Dilated colon

Difficulty swallowing

These symptoms are due to organ damage caused by the persistent presence of the parasites within the tissues of these organs. Chronic inflammation develops as the body reacts to the parasites; it affects the nerve cells or neurons in these tissues, causing electrical conduction changes in the heart (arrhythmias) and poor muscle tone in the intestines.

**Charcot-Marie-Tooth Disease**

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in the United States. The disease is named for the three physicians who first identified it in 1886 - Jean-Martin Charcot and Pierre Marie in Paris, France, and Howard Henry Tooth in Cambridge, England. CMT, also known as hereditary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy, comprises a group of disorders that affect peripheral nerves. The peripheral nerves lie outside the brain and spinal cord and supply the muscles and sensory organs in the limbs. Disorders that affect the peripheral nerves are called peripheral neuropathies.

The neuropathy of CMT affects both motor and sensory nerves. A typical feature includes weakness of the foot and lower leg muscles, which may result in foot drop and a high-stepped gait with frequent tripping or falls. Foot deformities, such as high arches and hammertoes (a condition in which the middle joint of a toe bends upwards) are also characteristic due to weakness of the small muscles in the feet. In addition, the lower legs may take on an "inverted champagne bottle" appearance due to the loss of muscle bulk. Later in the disease, weakness and muscle atrophy may occur in the hands, resulting in difficulty with fine motor skills.

Onset of symptoms is most often in adolescence or early adulthood, however presentation may be delayed until mid-adulthood. The severity of symptoms is quite variable in different patients and even among family members with the disease. Progression of symptoms is gradual. Pain can range from mild to severe, and some patients may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Although in rare cases patients may have respiratory muscle weakness, CMT is not considered a fatal disease and people with most forms of CMT have a normal life expectancy.

There are many forms of CMT disease, including CMT1, CMT2, CMT3, CMT4, and CMTX.

**CMT1**, caused by abnormalities in the myelin sheath, has three main types.**CMT1A** is an autosomal dominant disease resulting from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP-22). The PMP-22 protein is a critical component of the myelin sheath. An overabundance of this gene causes the structure and function of the myelin sheath to be abnormal. Patients experience weakness and atrophy of the muscles of the lower legs beginning in adolescence; later they experience hand weakness and sensory loss. Interestingly, a different neuropathy distinct from CMT1A called **hereditary neuropathy with predisposition to pressure palsy (HNPP)** is caused by a deletion of one of the PMP-22 genes. In this case, abnormally low levels of the PMP-22 gene result in episodic, recurrent demyelinating neuropathy.

**CMT1B** is an autosomal dominant disease caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (P0), which is another critical component of the myelin sheath. Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code. To date, scientists have identified more than 30 different point mutations in the P0 gene. As a result of abnormalities in P0, CMT1B produces symptoms similar to those found in CMT1A. The gene defect that causes CMT1C, which also has symptoms similar to those found in CMT1A, has not yet been identified.

**CMT2** results from abnormalities in the axon of the peripheral nerve cell rather than the myelin sheath. There are many subtypes of CMT2, designated by the letters from A-L. Each subtype is characterized by the mode of inheritance and associated clinical features. The genetic loci have been identified for some subtypes. Recently, a mutation was identified in the gene that codes for the kinesin family member 1B-beta protein in families with CMT2A. Kinesins are proteins that act as motors to help power the transport of materials along the train tracks (microtubules) of the cell. Another recent finding is a mutation in the neurofilament-light gene, identified in a Russian family with CMT2E. Neurofilaments are structural proteins that help maintain the normal shape of a cell.

**CMT3** or **Dejerine-Sottas disease** is a severe demyelinating neuropathy that begins in infancy. Infants have severe muscle atrophy, weakness, and sensory problems. This rare disorder can be caused by a specific point mutation in the P0 gene or a point mutation in the PMP-22 gene.

**CMT4** comprises several different subtypes of autosomal recessive demyelinating motor and sensory neuropathies. Each neuropathy subtype is caused by a different genetic mutation, may affect a particular ethnic population, and produces distinct physiologic or clinical characteristics. Patients with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk. The gene abnormalities responsible for CMT4 have yet to be identified.

**CMTX** is an X-linked dominant disease and is caused by a point mutation in the connexin-32 gene on the X chromosome. The connexin-32 protein is expressed in Schwann cells-cells that wrap around nerve axons, making up a single segment of the myelin sheath. This protein may be involved in Schwann cell communication with the axon. Males who inherit one mutated gene from their mothers show moderate to severe symptoms of the disease beginning in late childhood or adolescence (the Y chromosome that males inherit from their fathers does not have the connexin-32 gene). Females who inherit one mutated gene from one parent and one normal gene from the other parent may develop mild symptoms in adolescence or later or may not develop symptoms of the disease at all.

**Chediak-Higashi Syndrome**

Chediak-Higashi's syndrome is a very rare recessive autosomal disease. Patients present with a combination of oculocutaneous albinism with decreased pigmentation, silvery-blond hair, hepatosplenomegaly, ganglionic hypertrophia and recurrent pyogenic cutaneo-respiratory infections. These signs result from functional anomalies of polynuclear cells, which contain large characteristic lysosomal inclusions, and from Natural Killer (NK) lymphocytes deficiency. Vital prognostic is very severe. The _CHS_ gene was localised to the long arm of chromosome 1, 1q42.1-q42.2. An animal model of the disease, the beige mouse, allowed the discovery of a gene encoding LYST protein, whose function remains unknown.

**Chiari-Frommel Syndrome**

Chiari-Frommel syndrome is a rare condition where galactorrhea and amenorrhea continues for an abnormal length of time (generally longer than 6 months) after giving birth.

The list of signs and symptoms mentioned in various sources for Chiari-Frommel syndrome includes the 12 symptoms listed below:

Galactorrhea

Absence of menstruation

Lack of ovulation

Persistent nipple discharge

Emotional lability

Headache

Backache

Abdominal pain

Vision impairment

High prolactin level

Low urinary estrogen level

Low urinary gonadotropin level

**Chondrodysplasia Punctata**

Chondrodysplasia punctata is a group of inherited disorder affecting the skeleton, skin, eyes and mental function. The disorders are characterized mainly by stippled epiphyses (abnormal calcification near joints) during infancy. The various forms of the disorders have varying severity with some causing death before or soon after birth. The range of symptoms also various between the various types.

The list of signs and symptoms mentioned in various sources for Chondrodysplasia punctata includes the 10 symptoms listed below:

Retarded growth

Short limbs

Cataracts

Dry skin

Scaly skin

Large skin pores

Patches of coarse hair

Patches of dry hair

Mild mental retardation

Stippled epiphyses

**Choreatic Disorders**

Acquired and hereditary conditions which feature chorea as a primary manifestation of the disease process.

Chorea is characterized by brief, semi-directed, irregular movements that are not repetitive or rhythmic, but appear to flow from one muscle to the next.

These 'dance-like' movements of chorea often occur with athetosis, which adds twisting and writhing movements. Walking may become difficult, and include odd postures and leg movements.

Unlike ataxia, which affects the quality of voluntary movements, or parkinsonism, which is a hindrance of voluntary movements, the movements of chorea and ballism occur on their own, without conscious effort. Thus, chorea is said to be a hyperkinetic movement disorder.

When chorea is serious, slight movements will become thrashing motions; this form of severe chorea is referred to as ballism or ballismus.

**Churg-Strauss Syndrome**

Churg-Strauss syndrome is one of many forms of vasculitis. Vasculitis diseases are characterized by inflammation of blood vessels. Churg-Strauss syndrome, in particular, occurs in patients with a history of asthma or allergy and features inflammation of blood vessels (also referred to as angiitis) in the lungs, skin, nerves, and abdomen. The blood vessels involved in Churg-Strauss syndrome are small arteries and veins.

Churg-Strauss syndrome causes fever, weight loss, and sinus or nasal passage inflammation in the patient with asthma. Fatigue is common. Sometimes the asthma actually improves somewhat as the disease intensifies elsewhere. Cough, shortness of breath, and chest pain can occur as the lungs are affected by vasculitis.

Skin lumps, called nodules, can appear on the extremities. Diarrhea and pain in the belly occur due to blood vessel inflammation within the abdomen. The bladder and prostate gland can become inflamed.

Numbness or weakness of the extremities is the result of nerve injury from the vasculitis. If the brain is affected, seizures or confusion can occur.

**Colonic Pseudo-Obstruction**

Intestinal Pseudo-obstruction is a clinical syndrome caused by severe impairment in the ability of the intestines to push food through. It is characterised by the signs and symptoms of intestinal obstruction without any lesion in the intestinal lumen.[1] Clinical features can include abdominal pain, nausea, severe distension, vomiting, dysphagia, diarrhoea and constipation, depending upon the part of the gastrointestinal tract involved.[2] The condition can begin at any age and it can be a primary condition (idiopathic or inherited) or caused by another disease (secondary).[3]

It can be chronic[4] or acute.[5]

In primary chronic intestinal pseudo-obstruction (the majority of chronic cases), the condition may be caused by a injury to the smooth muscle (myopathic) or the nervous system (neuropathic) of the gastrointestinal tract.[6]

In some cases there appears to be a genetic association.[7] One form has been associated with DXYS154.[8]

Secondary chronic intestinal pseudo-obstruction can occur as a consequence of a number of other conditions, including Kawasaki disease,[9] Parkinson's disease, Chagas' Disease, Hirschsprung's Disease, Intestinal Hypoganglionosis, collagen vascular diseases, endocrine disorders and use of certain medications.[6] The term may be used synonymously with Enteric neuropathy if a neurological cause is suspected.

The list of signs and symptoms mentioned in various sources for Ogilvie's syndrome (Colonic Pseudo-Obstruction) includes the 10 symptoms listed below:

Abdominal distention

Hyperactive bowel sounds

High pitched bowel sounds

Abdominal tenderness

Nausea

Vomiting

Fever

Constipation

Diarrhea

Perforation

**Craniofacial Dysostosis**

Craniofacial dysostosis type 1 is a rare genetic disorder characterized by premature joining of certain skull bones during development which has an impact on the shape of the head and face. Features include poor vision, hypoplasia of maxilla an impaired hearing.

The list of signs and symptoms mentioned in various sources for Craniofacial dysostosis type 1 includes the 21 symptoms listed below:

Ocular proptosis

Shallow orbits

Divergent strabismus

Widely spaced eyes

Frontal bossing

Conjunctivitis

Kratitis

Poor visual acuity

Optic atrophy

Nystagmus

Hypoplasia of maxilla

Curved parrot-like nose

Inverted V-shaped palate

Conductive hearing loss

Premature joining of skull bones

Premature closing of coronal sutures

Premature closing of lambdoid sutures

Premature closing of sagittal sutures

Short anteposterior dimensions of the skull

Wide lateral dimensions of the skull

Upper airway obstruction

**De Lange Syndrome**

De Lange syndrome is a rare genetic disorder with multiple malformations and mental retardation of unknown origin.

de Lange syndrome is recognized by the presence of:

Prenatal and postnatal growth retardation;

Delayed development and mental retardation;

Abnormally small head (microcephaly);

Hair low on the nape of the neck;

Characteristic facial appearance with

Low-set ears,

Hair well down onto the forehead,

Bushy eyebrows,

Eyebrows that meet in the middle (synophrys),

Unusually long eyelashes,

Depressed bridge of the nose,

Uptilted tip of the nose,

Forward-directed nostrils,

Protuberance of the upper jaw (maxillary prognathism),

"Carp-shaped" mouth, and

Small, widely spaced teeth; and

Upper limb anomalies with flat spadelike hands with a "simian" (single transverse) palmar crease and short tapering fingers.

The great majority of children with de Lange syndrome have no known family history of the disorder. There are, however, some reports of familial cases. These reports suggest autosomal dominant transmission with a mildly affected parent having a more seriously affected child. The chance is from 2 to 5% that a child whose sib has de Lange syndrome will also have the syndrome.

In familial de Lange syndrome, a gene on chromosome 5 is mutated. The gene is NIPBL (Nipped B-like). It is so named for its counterpart in fruit flies (Nipped B) which look to have a small nip taken out of their wings. In both fruit flies and human beings, the gene appears to be involved in the very early stages of embryonic development. NIPBL contains the information needed to make a protein that helps to switch on a number of other genes.

The syndrome is named for a Dutch physician, de Lange (whose first name was Cornelia). She was professor of pediatrics in Amsterdam. In 1933, Dr. de Lange reported 2 infant girls with mental deficiency and other features now associated with the syndrome.

The syndrome is also called the Brachmann-de Lange syndrome, thanks to Dr. John Opitz who has recounted that: "In the fall of 1963...the former head of the...Libraries, came to ask my advice on what to do with a series of volumes of the Jahrbuch fur Kinderheilkunde, which had been damaged...by a burst water pipe. In particular, she was upset by volume 84, dated 1916, the pages of which were completely glued together except for one place, the article beginning on p. 225. I was startled to find out that here was an article on the Cornelia de Lange syndrome written 17 years before de Lange's first paper of 1933. The author, Dr. W. Brachmann, whose subsequent fate is unknown to me, was then a young physician in training, who apologized that his study of this remarkable case was interrupted by sudden orders to report for active duty (in the German Army)."

**Dementia, Vascular**

Vascular dementia is a common form of dementia in older persons that is due to cerebrovascular disease, usually with stepwise deterioration from a series of small strokes and a patchy distribution of neurologic deficits affecting some functions and not others. Symptoms include confusion, problems with recent memory, wandering or getting lost in familiar places, loss of bladder or bowel control (incontinence), emotional problems such as laughing or crying inappropriately, difficulty following instructions, and problems handling money. The damage is typically so slight that the change is noticeable only as a series of small steps. However, over time, as more small blood vessels in the brain are blocked, there is noticeable gradual mental decline. Vascular dementia commonly begins between the ages of 60 and 75 and affects men more often than women. Also known as multi-infarct dementia.

**Dermatitis****Herpetiformis**

Dermatitis herpetiformis (DH) is a subepidermal bullous disease characterized by chronic recurrence of itchy, erythematous papules, urticarial wheals and grouped vesicles that appear symmetrically on the extensor surfaces, buttocks and back. Children and young adults are mostly affected. Prevalence is estimated about 1 to 4 cases/10 000, with incidence ranging from 0,9 (Italy) to 2,6 (Northern Ireland) new cases/100 000/year. The disease is the cutaneous expression of a gluten-sensitive enteropathy identifiable with celiac disease. The clinical and histological pictures of both entities are quite similar. Granular IgA deposits at the dermo-epidermal junction, neutrophils and eosinophils together with activated CD4+ Th2 lymphocytes are supposed to represent the main immune mechanisms that co-operate in the pathogenesis of the disease. A strict gluten withdrawal from diet represents the basis for treatment.

**Diffuse Cerebral Sclerosis of Schilder**

Balo's concentric sclerosis(Diffuse Cerevral Sclerosis of Schilder) is the demyelination of the brain producing a variety of symptoms depending on the area of the brain affected.

The list of signs and symptoms mentioned in various sources for Balo's concentric sclerosis includes the 7 symptoms listed below:

Progressive spastic paralysis

Neurological symptoms

Paralysis

Intellectual impairment

Physiological impairment

Unsteady walking

Muscle wasting

**Duane Retraction Syndrome**

Duane syndrome is a congenital eye movement disorder in which there is miswiring of the eye muscles, causing some eye muscles to contract when they should not and other eye muscles not to contract when they should. People with the syndrome have a limited (and sometimes no) ability to move the eye outward toward the ear (to abduct the eye) and, in most cases, a limited ability to move the eye inward toward the nose (to adduct the eye). Often, when the eye moves toward the nose, the eyeball also pulls into the socket (retracts), the eye opening narrows and, in some cases, the eye moves upward or downward. Many patients with Duane syndrome turn their face to maintain binocular vision and compensate for improper turning of the eyes.

Duane syndrome is unilateral (with only one eye affected) in about 80% of cases. The remaining 20% of cases are bilateral (with both eyes affected) with one eye usually more severely affected than the other.

Duane syndrome is isolated (it is the only disorder the individual has) in 70% of cases. The remaining 30% of the time Duane syndrome occurs in association with malformations of the skeleton, ears, eyes, kidneys and nervous system and as a component of Okihiro syndrome (an association of Duane syndrome with forearm malformation and hearing loss), Wildervanck syndrome (fusion of neck vertebrae and hearing loss), Holt-Oram syndrome (abnormalities of the upper limbs and heart), Morning Glory syndrome (abnormalities of the optic disc or "blind spot"), and Goldenhar syndrome (malformation of the jaw, cheek and ear, usually on one side of the face).

Clinically, Duane syndrome is often subdivided into three types:

Type 1 - The affected eye, or eyes, has limited ability to move outward toward the ear, but the ability to move inward toward the nose is normal or nearly so. The eye opening narrows and the eyeball pulls in when looking inward toward the nose, however the reverse occurs when looking outward toward the ear. About 78% of all Duane syndrome cases are Type 1.

Type 2 - The affected eye, or eyes, has limited ability to move inward toward the nose, but the ability to move outward toward the ear is normal or nearly so. The eye opening narrows and the eyeball pulls in when looking inward toward the nose. About 7% of all Duane syndrome cases are Type 2.

Type 3 - The affected eye, or eyes, has limited ability to move both inward toward the nose and outward toward the ears. The eye opening narrows and the eyeball pulls in when looking inward toward the nose. About 15% of all Duane syndrome cases are Type 3.

Each of these three types can be further classified into three subgroups, depending on where the eyes are when the individual looks straight (the primary gaze):

Subgroup A - The affected eye is turned inward toward the nose (esotropia).

Subgroup B - The affected eye is turned outward toward the ear (exotropia).

Subgroup C - The eyes are in a straight, primary position.

Duane syndrome is due to a miswiring of the medial and the lateral rectus muscles, the muscles that move the eyes. Also, patients with the syndrome lack the abducens nerve, the sixth cranial nerve, which is involved in eye movement. Genetic and environmental factors are believed to play a role in Duane syndrome. The syndrome can be inherited as an autosomal dominant or recessive trait. Genes involved in the development of Duane syndrome are located on chromosomes 2q13 and 8q13.

Other names for Duane syndrome include: congenital retraction syndrome, Duane retraction syndrome, eye retraction syndrome, retraction syndrome, and Stilling-Turk-Duane syndrome.

**Dupuytren's Contracture**

A Dupuytren's contracture is a localized formation of scar tissue around the tendons that flex the fingers beneath the skin of the palm of the hand. The scarring accumulates in a tissue (palmar fascia) that normally covers the tendons that pull the fingers to grip. As a Dupuytren's contracture progresses, more of the fascia becomes thickened and shortened. Dimpling and puckering of the skin over the area eventually occurs and ultimately can make it impossible to fully extend the hand (as in laying it flat on a tabletop).

A Dupuytren's contracture initially may cause only a minor painless lump in the palm of the hand near the base of the finger(s). A Dupuytren's contracture most commonly affects the ring (fourth) finger, but it can affect any finger. A Dupuytren's contracture can also affect one or both hands.

As a Dupuytren's contracture progresses, it can lead to an inability to fully extend the affected finger from the flexed position. This can result in a loss of normal grasping.

A Dupuytren's contracture is seldom associated with much, if any, pain unless the affected fingers are inadvertently forcefully hyperextended.

**Dysautonomia, Familial**

Familial dysautonomia is a genetic disorder of the autonomic nervous system, affecting especially Ashkenazi Jewish children. Familial dysautonomia is inherited in an autosomal recessive manner and is due to mutation in the IKBKAP gene on chromosome 9q31. Dysautonomia refers to the dysfunction of the autonomic nervous system. Familial dysautonomia is symbolized DYS.

The features of familial dysautonomia include lack of tears, emotional lability, relative indifference to pain, increased sweating, cold hands and feet, red blotching of the skin, corneal anesthesia and corneal ulcers, paroxysmal hypertension, taste deficiency and lack of the fungiform papillae. Scoliosis may be severe. The disease may be manifest in first days of life. Two-thirds of patients die before age 20.

The syndrome was first described by Riley, Day, Greeley, and Langford in 1949. It is also called the Riley-Day syndrome after the American pediatricians Conrad Riley (1913-) and Richard L. Day (1905-1989). For some odd reason, Greeley and Langford were omitted from the eponym. An alternative name for the syndrome is hereditary sensory & autonomic neuropathy III (HSAN III).

**Ebstein's Anomaly**

Ebstein's malformation is a rare congenital cardiac anomaly characterized by rotational displacement of the septal and inferior leaflets of the tricuspid valve such that they are hinged within the right ventricle, rather than as expected at the atrioventricular junction. Prevalence is estimated at 1/50,000-1/200,000. Both sexes are equally affected. Clinical presentation is heterogeneous and depends on the severity of the lesion (extent of tethering of the antero-superior leaflet across the normal valvar orifice), and the degree of dysfunction of the right ventricle. Patients with minor forms of the disease remain asymptomatic or may present with an incidental murmur, exertional dyspnea, fatigue, or palpitations. Those with severe forms can present at various ages with arrhythmias, cyanosis, and sometimes cardiac failure. Those with the most severe malformations present as neonates, often with so-called ``wall-to-wall'' hearts. During adulthood, supraventricular tachycardia can also be observed, a proportion of patients also having Wolff-Parkinson-White syndrome (see this term). The malformation is often associated with other cardiac lesions, such as atrial or ventricular septal defects, patency of the arterial duct, and pulmonary stenosis. Etiology is unknown. In some cases, maternal ingestion of lithium was associated with the disease. Diagnosis is based on cross-sectional or 3D echocardiography, which reveals the rotational displacement of the leaflets, the extent of abnormal tethering of the antero-superior leaflet, the extent of thinning of the atrialized inlet component of the right ventricle, and the degree of regurgitation or stenosis of the abnormal valve. The electrocardiogram can reveal right atrial hypertrophy, right bundle branch block, and supraventricular tachycardia. Radiography shows any cardiomegaly, and cardiac MRI shows the full extent of the valvar abnormalities. The major differential diagnosis, particularly during fetal life, is dysplasia of the leaflets of the tricuspid valve. This, as can Ebstein's malformation if associated with pulmonary atresia, can lead to gross thinning of the walls of the right ventricle which should not be confused with Uhl's anomaly (see this term). The severest forms of Ebstein's malformation can produce an imperforate tricuspid valve, which must be distinguished from tricuspid atresia (see this term). Antenatal diagnosis is now possible with fetal echocardiography that reveals hydrops fetalis. Medical treatment relies on inotropic agents (in case of cardiac failure) and antiarrhythmic drugs (in case of tachyarrhythmia). Definitive treatment is surgical and consists of reconstructive surgery prior to the onset of cardiac failure. If the valve is too malformed, replacement is the only option. Asymptomatic patients, and patients with mild forms of the disease, have a normal life expectancy. Patients with severe forms of the disease, particularly those presenting during the fetal period or as neonates, have an increased risk of death due to cardiac failure, including at birth or during physical exercise.

**Ehlers-Danlos Syndrome**

Ehlers-Danlos syndromes are a group of disorders which share common features including easy bruising, joint hypermobility (loose joints), skin that stretches easily (skin hyperelasticity or laxity), and weakness of tissues.

The Ehlers-Danlos syndromes are inherited in the genes that are passed from parents to offspring. They are categorized according to the form of genetic transmission into different types with many features differing between patients in any given type. The fragile skin and loose joints is often a result of abnormal genes that produce abnormal proteins that confer an inherited frailty of collagen (the normal protein "glue" of our tissues).

In 2001, researchers discovered a new form of Ehlers-Danlos syndrome that is caused by an inherited abnormality in a protein other than collagen that also normally plays a role in binding together the cells of our tissues (including the skin, tendons, muscle, and blood vessels). Abnormalities in this protein, called tenascin, also lead to a form of Ehlers-Danlos syndrome. Researchers suspect that tenascin could play a role in regulating the normal distribution of collagen in the connective tissues of the body.

**Classical type  
(formerly types I & II)**

Marked joint hypermobility, skin hyperextensibility (laxity), and fragility are characteristic of the classic type of Ehlers-Danlos syndrome. The smooth, velvety skin is fragile and tears or bruises easily with minor trauma. Joint dislocations and scoliosis are common. Joint instability can lead to sprains and strains. This classical type is inherited as an autosomal dominant genetic trait (directly passed on from one parent to child).

**Hypermobility type****  
(formerly type III)**

Joint hypermobility is the major manifestation of this form of Ehlers-Danlos syndrome. Any joint can be affected, and dislocations are frequent. This type is also inherited as an autosomal dominant genetic trait.

**Vascular type****  
(formerly type IV, the arterial form)**

In this form of Ehlers-Danlos syndrome, spontaneous rupture of arteries and bowel is a serious manifestation that can lead to death. Clubfoot can be present at birth. Skin laxity is of varying degrees. Veins can be very visible through the skin. It is primarily inherited as an autosomal dominant (directly passed on from one parent to child) genetic trait, but recessive (not seen in family members or only in one generation of members of the same family, meaning that an individual must inherit two copies of the mutation, one from each parent) trait inheritance has been described.

**Kyphoscoliosis type****  
(formerly type VI)**

Fragile globe of the eyes, significant skin and joint laxity, and severe curvature of the spine (scoliosis) are typical features. Its inheritance pattern is autosomal recessive.

**Arthrochalsia type****  
(formerly type VIIB, arthrochalasis multiplex congenita)**

Patients are short in height and severely affected by joint laxity and dislocations. Skin involvement is variable. Both utosomal dominant and recessive inheritance is possible. A skin biopsy can be used to diagnose this disorder.

**Dermatosparaxis type****  
(formerly type VIIC)**

Patients have severely fragile skin that is soft and doughy with sagging and folding. This rare form of Ehlers-Danlos syndrome can be diagnosed with a skin biopsy.

**Tenascin-X deficient type**

Joint hypermobility, hyperelastic skin, and fragile tissue are seen. Patients with this type lack the multiple shrinking (atrophied) scars in the skin that are often seen in classic Ehlers-Danlos. It is inherited as an autosomal recessive genetic trait.

Other rare variant types have been reported in single families.

**Eisenmenger Complex**

Eisenmenger syndrome is a condition that affects blood flow from the heart to the lungs in some babies who have structural problems of the heart.

Eisenmenger syndrome is caused by a defect in the heart. Most often, babies with this condition are born with a hole between the two pumping chambers - the left and right ventricles - of the heart (ventricular septal defect). The hole allows blood that has already picked up oxygen from the lungs to flow back into the lungs, instead of going out to the rest of the body.

Other heart defects that can lead to Eisenmenger syndrome include:

Atrioventricular canal defect

Atrial septal defect

Cyanotic heart disease

Patent ductus arteriosus

Truncus arteriosus

Over time, increased blood flow can damage the small blood vessels in the lungs. This causes high blood pressure in the lungs. As a result, the blood backs up and does not go to the lungs to pick up oxygen. Instead, the blood goes from the right side to the left side of the heart, allowing oxygen-poor blood to travel to the rest of the body.

Eisenmenger syndrome usually develops before a child reaches puberty. However, it also can develop in young adulthood.

Symptoms are :

Bluish lips, fingers, toes, and skin (cyanosis)

Chest pain

Coughing up blood

Dizziness

Fainting

Feeling tired

Shortness of breath

Stroke

Swelling in the joints caused by too much uric acid (gout)

Bleeding (hemorrhage) in the brain

Congestive heart failure

Gout

Heart attack

Hyperviscosity (sludging of the blood because it is too thick with blood cells)

Infection (abscess) in the brain

Kidney failure

Poor blood flow to the brain

Stroke

Sudden death

**Ellis-Van Creveld Syndrome**

Ellis-van Creveld syndrome is a type of short stature with striking shortening of the ends of the extremities (arms and legs), polydactyly (extra digits), fusion of bones in the wrist, dystrophy (abnormal growth) of the fingernails, change in the upper lip variously called 'partial hare-lip,' 'lip-tie,' etc., and cardiac (heart) malformations. The teeth may already be erupted at birth (natal teeth) and fall out prematurely.

The Ellis-van Creveld (EvC) syndrome was first described by Drs. Richard W. B. Ellis of Edinburgh and Simon van Creveld of Amsterdam. Each had a patient with this syndrome, as they had discovered when they met in the same train compartment on the way to a pediatrics conference in England in the late 1930s.

EvC is common in an inbred religious isolate, the Old Order Amish, in Lancaster County, Pennsylvania; this reflects the fact that the EvC syndrome is a rare autosomal recessive trait. The Amish gene for EvC, located in chromosome band 4p16.1, has been identified, permitting premarital and pre-natal counseling.

EvC has been found to be due to mutations in EVC or in another gene dubbed EVC2. These two genes lie in a head-to-head configuration on the same chromosome. Affected individuals with mutations in EVC and EVC2 have the typical spectrum of features and are indistinguishable.

**Encephalitis**

Encephalitis, Rasmussen is a rare progressive neurological disorder that is characterized by intractable seizures and progressive neurologic deterioration. To be more precise, there are frequent and severe seizures (convulsions), progressive loss of motor skills and speech, hemiparesis (paralysis on one side of the body), encephalitis (inflammation of the brain),dementia, and mental deterioration. The disorder affects a single brain hemisphere (one side or the other of the brain but not both sides) and generally occurs in children under the age of 15.

The standard treatment for Rasmussen's encephalitis is surgery to remove or disconnect the affected part of the brain (hemispherectomy). Although anti-epileptic drugs may be prescribed initially, they are usually not effective in the long run in controlling the seizures. Alternative treatments may include plasmapheresis (the removal and reinfusion of blood plasma), ketogenic diet (high fat, low carbohydrate), and steroids (cortisone-like drugs).

The prognosis (outlook) for individuals with Rasmussen's encephalitis varies. Untreated, the disorder may lead to severe neurological deficits including mental retardation and paralysis. In some patients the surgery decreases the seizures. However, most patients are left with some paralysis and speech deficits.

Rasmussen's encephalitis is believed due to a number of causes. In some cases there is an abnormal immune attack against what is called the glutamate receptor GluR3. Antibodies directed against GluR3 have been identified in patients. (Reference: Rogers et al.: Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265: 648-651, 1994.) Plasmapheresis (skimming off the blood plasma) has been tried (to remove the GluR3) but the improvement was short-lived.

Rasmussen's encephalitis is also known as chronic focal encephalitis or chronic progressive epilepsia paritalis continua of childhood.

**Enchondromatosis**

Enchondromatosis is a condition characterized by multiple enchondromas - benign masses of cartilage growing within bones. The enchondromas can deform and shorten a limb and predispose to a fracture. The condition can be caused by a mutation in the gene for the parathyroid hormone receptor (PTHR1). Also known as Ollier disease.

**Epidermal Necrolysis, Toxic**

Toxic epidermal necrolysis (TEN) is an acute and severe skin disease with clinical and histological features characterized by the destruction and detachment of the skin epithelium and mucous membranes. Annual incidence is around 1/500,000. Females are more often affected than males. Onset may occur at any age, but the risk increases after 40 years. Three subforms have been described according to the percentage of the body surface area affected: Stevens-Johnson syndrome (10%; see this term), Lyell syndrome (=30%; see this term) and an intermediate form (10-29%). The initial manifestations are nonspecific: a seemingly banal rash, fever, and a burning sensation involving the eyes, mouth and genitalia. The rash rapidly progresses to become vesicular and bullous on the face and body. The cutaneous vesicles aggregate and rupture under mild friction, revealing denuded red skin with seeping and pain. Mucous membrane lesions are present in 85 to 95% of patients with involvement, in order of frequency, of the oropharynx, eyes, genitalia and anus. Lesions are painful and lead to hypersalivation, feeding problems, photophobia, and burns following urination. High fever is a constant feature. Visceral manifestations are also frequent with hematological, respiratory and digestive involvement. In two thirds of cases, TEN is triggered by a clearly identifiable drug allergy. A dozen high risk drugs have been identified: allopurinol, anti-infective sulphonamide agents, lamotrigine, nevirapine, carbamazepine, phenobarbital, phenytoin, and oxicam-derived nonsteroidal anti-inflammatory drugs. In rare cases, the disease is associated with infections (in particular, _Mycoplasma pneumonia_) or bone marrow transplantation. The remaining 25-30% of cases are classed as idiopathic, but some of these cases may be associated with failure to identify the causative drug. The clinical diagnosis should be confirmed by skin biopsy, which will reveal epidermal necrosis and the absence of antibody deposits. The differential diagnosis should include chicken pox during the early stages of the disease, staphylococcal epidermolysis, staphylococcal scalded skin syndrome (associated with superficial skin peeling caused by a specific staphylococcal toxin and usually occurring in neonates), and, more rarely, autoimmune bullous diseases (excluded by examination of skin biopsies). In addition, the more limited forms of TEN are still often misdiagnosed as erythema multiforme major. Patients should be admitted to an intensive care or burns unit as soon as the diagnosis is suspected. The causative drug, together with any related compounds should be contraindicated for the patient and their close relatives (in case a genetic predisposition). No disease-modifying drugs have been shown be efficient in the treatment of TEN. The benefits of general corticotherapy and cyclosporine administration are still under evaluation. High-dose intravenous immunoglobulins are costly and appear to be of limited efficacy. Intensive symptomatic management is essential: a heated environment, analgesia, daily dressing changes, prevention of infections, and symptomatic intensive care measures (hydration, nutrition, and hyperbaric oxygen therapy). Reepithelialization is rapid (2-3 weeks). However, the prognosis for patients with extensive forms of TEN is poor (mortality rate: 20-25%). Sequelae are reported in over 80% of surviving patients with ocular sequelae being the most problematic as they tend to be severe and progressive. Other sequelae (cutaneous, genital, buccal/dental or bronchial problems) are generally easier to detect and treat.

**Facial Hemiatrophy**

Facial hemiatrophy is a syndrome characterized by slowly progressive unilateral atrophy of facial subcutaneous fat, muscle tissue, skin, cartilage, and bone. The condition typically progresses over a period of 2-10 years and then stabilizes.

Parry Romberg Syndrome(Progressive Facial Hemiatrophy) is the wasting away of one side of the face.

The list of signs and symptoms mentioned in various sources for Parry Romberg Syndrome includes the 21 symptoms listed below:

One-sided facial atrophy

Unilateral sunken eye

Unilateral sunken cheek

Pain

Migraine-like headaches

Trigeminal neuralgia

Seizures - starting in the opposite side of the body

Alopecia on affected side of face

Blanched hair on affected side of face

Atrophy of fat on affected side of face

Atrophy of subcutaneous tissue on affected side of face

Jacksonian epilepsy

Migraine

Degenerative brain lesions

Intracranial calcification

Sensory impairment on affected side of face

Excessive sweating on affected side of face

Tear duct dysfunction on affected side of face

Sunken eye on affected side of face

Sunken cheek on affected side of face

Trigeminal neuralgia on affected side of face

**Factor XII****Deficiency**

Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the _F12_ gene.[1]

Factor XII deficiency is rare disorder that is inherited in an autosomal recessive manner.[4] Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding.[4] Mice lacking the gene for factor XII, however, are less susceptible to thrombosis. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall. [5]

Factor XII does play an important role in clot formation during _in vitro_ measurements of the partial thromboplastin time, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor 11 deficiency.[4] As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result.[4] All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen.[4]

Normal or excess levels of factor XII can predispose towards greater risk of venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of plasmin.[6]

Hageman factor is also activated by Endotoxin, especially Lipid A.

**Factor XIII Deficiency**

Congenital factor XIII deficiency is an inherited bleeding disorder due to reduced levels and activity of factor XIII (FXIII) and characterized by hemorrhagic diathesis frequently associated with spontaneous abortions and defective wound healing. Factor XIII deficiency is one of the most rare coagulation factor deficiencies. Prevalence of homozygous forms is estimated at around 1/2,000,000. Both sexes are equally affected. Congenital FXIII deficiency can manifest at any age, but diagnosis is often made during infancy. Umbilical stump bleeding manifests in up to 80% of patients. Other common signs include intracranial hemorrhage (25-30%), soft tissue bleeding, bruising, hemarthroses (20%), and recurrent spontaneous abortions. In most cases, hemorrhages are delayed (12-36hr) after trauma or surgery. Patients may have poor wound healing. Acquired forms of the disease have also been reported in association with hepatic failure, inflammatory bowel disease (see this term), and myeloid leukemia. Congenital FXIII deficiency is usually caused by mutations in the _F13A1_gene (6p24.2-p23) encoding the catalytic A subunit, but mutations have also been found in the _F13B_ gene (1q31-q32.1) encoding the B subunit. Transmission is autosomal recessive. The phenotype is less severe when the _F13B_ gene is mutated. Diagnosis is based on quantitative FXIII activity measurement and antigen assays. Common clotting assays such as activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT) are normal and cannot be used for the screening. The clot solubility test may also be used (clot is stable for more than 24 hours in case of FXIII deficiency). Molecular testing is available, but unnecessary for diagnosis. Differential diagnoses mainly include the other congenital coagulation factor deficiencies: fibrinogen, factors II, V, VII, X, XI, VIII, IX (see these terms). Antenatal diagnosis is possible if the causal mutations have previously been identified in the family. Factor XIII concentrates or fresh frozen plasma (when FXIII concentrates are not available) is usually used for the treatment of bleedings. Prophylactic therapy with FXIII concentrate should be indicated to prevent recurrent bleedings such as intracranial hemorrhage. Intracranial hemorrhage can be life threatening, but prognosis is favorable if adequate treatment is provided.

**Fanconi****Anemia**

Fanconi anemia is a rare, inherited disease that adversely affects all the elements of bone marrow and is associated with malformations of the heart, kidney, and limbs, as well as pigmentary changes of the skin. Fanconi anemia predisposes a person to cancer, particularly to a disturbance of bone marrow growth called myelodysplasia and to acute myeloid leukemia. Patients also tend to develop cancers in areas of the body where cells normally reproduce rapidly, such as the mouth, the esophagus, the intestinal and urinary tracts, and the reproductive organs. Fanconi anemia is most common in Ashkenazi Jews. Mutations in multiple different genes can cause the disease, which is inherited as an autosomal recessive trait.

FA is the result of a genetic defect in a cluster of proteins responsible for DNA repair. As a result, the majority of FA patients develop cancer, most often acute myelogenous leukemia, and 90% develop bone marrow failure (the inability to produce blood cells) by age 40. About 60-75% of FA patients have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% of FA patients have some form of endocrine problem, with varying degrees of severity. Median age of death was 30 years in 2000.[2]

Many patients eventually develop acute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers.[9] Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood.

The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. For instance, 90% of the Ashkenazi children born with Fanconi's have no thumbs. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects, such as microcephaly (small head).

**Felty's Syndrome**

Felty's syndrome is a complication of long-standing rheumatoid arthritis. Felty's syndrome is defined by the presence of three conditions: rheumatoid arthritis, an enlarged spleen (splenomegaly), and an abnormally low white blood count. Felty's syndrome is uncommon. It affects less than 1% of patients with rheumatoid arthritis.

Some patients with Felty's syndrome have more infections, such as pneumonia or skin infections, than the average person. This increased susceptibility to infections is attributed to the low white blood counts that are characteristic of Felty's syndrome. Ulcers in the skin over the legs can complicate Felty's syndrome.

The cause of Felty's syndrome is not known. Some patients with rheumatoid arthritis develop Felty's syndrome but most do not. White blood cells are produced in the bone marrow. There seems to be an active bone marrow function in patients with Felty's syndrome, producing white cells, despite the low numbers of circulating white blood cells. White cells may be stored excessively in the spleen of a patient with Felty's syndrome. This is especially true in patients with Felty's syndrome that have antibodies against the particular type of white blood cells usually affected (cells called granulocytes or neutrophils).

**Fibrous Dysplasia, Polyostotic**

Polyostotic fibrous dysplasia is a disorder that features the replacement of multiple areas of bone by fibrous tissue, which may cause fractures and deformity of the legs, arms, and skull. A genetic disorder that is characterized by polyostotic fibrous dysplasia along with skin pigmentation and hormonal problems, with premature sexual development, is known as McCune-Albright's syndrome. The flat areas of increased skin pigment are called caf' au lait spots. The hormonal problems that can be related to polyostotic fibrous dysplasia include early puberty (with premature menstrual bleeding and development of breasts and pubic hair), thyroid abnormalities, and an increased rate of growth. Also known as McCune-Albright syndrome.

**Fox-Fordyce Disease**

Fox–Fordyce disease, or apocrine miliaria, is a chronic blockage of the sweat gland ducts with a secondary, non-bacterial inflammatory response to the secretions and cellular debris in the cysts.[1]:709 Hidradenitis is very similar, but tends to have a secondary bacterial infection so that pus-draining sinuses are formed. It is a very devastating skin disease that does not have universally curative treatments. Many that have this disease avoid sweat-inducing activities and prefer swimming as their mode of exercise.

The apocrine glands (think sweat glands) are the site of the Fox-Fordyce disease. Lesions can be found at the sweat glands in addition to periareolar, inframammary and pubic areas. Lesions can be any shape (smooth, dome-shaped, etc.) and range from flesh-colored to red and sweating is often absent in the areas that are affected. Hair follicles can become damaged as well and can result in hair loss in the affected area.**  
**

**Friedreich Ataxia**

Friedreich ataxia is characterized by difficulties to coordinate movements, associated with neurological signs (dysarthria, loss of reflexes, decrease of deep sensation, pes cavus and scoliosis), cardiomyopathy and sometimes diabetes mellitus. In France prevalence is estimated to 1 in 50,000 and males and females are equally affected. Onset often occurs in childhood or adolescence, but also sometimes in adulthood. It is transmitted as an autosomal recessive trait. The causative gene is the _FRDA_ gene and codes for frataxin. Diagnosis can be made by genetic testing. The disease is due to a frataxin deficiency, which affects the mitochondrial function and the energetic metabolism of the cell. New treatments restoring mitochondrial functions are currently being assessed. Management should address the neurological and cardiological disorders as well as diabetes mellitus. Functional rehabilitation plays a predominant role in the management of the disease. Friedreich ataxia is is progressive, with an inability to walk alone 10 to 20 years after the disease onset.

**Fusobacterium**

Fusobacterium is a genus of anaerobic, Gram-negative bacteria, similar to Bacteroides. Individual cells are rod-shaped baccilli with pointed ends.[1] Strains of Fusobacterium contribute to several human diseases, including periodontal diseases, Lemierre's syndrome, and topical skin ulcers. Although older resources have stated that Fusobacterium is a common occurrence in the human oropharynx, the current consensus is that Fusobacterium should always be treated as a pathogen.[2] In 2011, researchers discovered that this bacteria flourishes in colon cancer cells, and is often also associated with ulcerative colitis, although researchers have not determined if the organism actually causes these diseases or if it simply flourishes in the environment these diseases create.[3]

In contrast to Bacteroides spp., Fusobacteria have a potent lipopolysaccharide.

Clindamycin was the most active antibiotic against Fusobacterium species, followed by chloramphenicol, carbenicillin, and cefoperazone (which were about equally active) and then cefamandole.[4]

**Gardner Syndrome**

Familial adenomatous polyposis (FAP) is an inherited disorder characterized by cancer of the large intestine (colon) and rectum. People with the classic type of familial adenomatous polyposis may begin to develop multiple noncancerous (benign) growths (polyps) in the colon as early as theirteenage years. Unless the colon is removed, these polyps will become malignant (cancerous). The average age at which an individual develops colon cancer in classic familial adenomatous polyposis is 39 years. Some people have a variant of the disorder, called attenuated familial adenomatous polyposis, in which polyp growth is delayed. The average age of colorectal cancer onset for attenuated familial adenomatous polyposis is 55 years.

In people with classic familial adenomatous polyposis, the number of polyps increases with age, and hundreds to thousands of polyps can develop in the colon. Also of particular significance are noncancerous growths called desmoid tumors. These fibrous tumors usually occur in the tissue covering the intestines and may be provoked by surgery to remove the colon. Desmoid tumors tend to recur after they are surgically removed. In both classic familial adenomatous polyposis and its attenuated variant, benign and malignant tumors are sometimes found in other places in the body, including the duodenum (a section of the small intestine), stomach, bones, skin, and other tissues. People who have colon polyps as well as growths outside the colon are sometimes described as having Gardner syndrome.

A milder type of familial adenomatous polyposis, called autosomal recessive familial adenomatous polyposis, has also been identified. People with the autosomal recessive type of this disorder have fewer polyps than those with the classic type. Fewer than 100 polyps typically develop, rather than hundreds or thousands. The autosomal recessive type of this disorder is caused by mutations in a different gene than the classic and attenuated types of familial adenomatous polyposis.

From early adolescence and onwards, patients with this condition develop hundreds to thousands of polyps. These may bleed, leading to blood in the stool. If the blood is not visible, it is still possible for the patient to develop anemia due to gradually developing iron deficiency. If malignancy develops, this may present with weight loss, altered bowel habit, or even metastasis to the liver or elsewhere.

The genetic determinant in familial polyposis may also predispose carriers to other malignancies, e.g., of the duodenum and stomach. Other signs that may point to FAP are pigmented lesions of the retina ("CHRPE - congenital hypertrophy of the retinal pigment epithelium"), jaw cysts, sebaceous cysts, and osteomata (benign bone tumors). The combination of polyposis, osteomas, fibromas and sebaceous cysts is termed Gardner's syndrome (with or without abnormal scarring).[1]

**Gaucher Disease**

Gaucher disease is an inherited disorder that affects many of the body's organs and tissues. The signs and symptoms of this condition vary widely among affected individuals. Researchers have described several types of Gaucher disease based on their characteristic features.

**Type 1 Gaucher disease** is the most common form of this condition. Type 1 is also called non-neuronopathic Gaucher disease because the brain and spinal cord (the central nervous system) are usually not affected. The features of this condition range from mild to severe and may appear anytime from childhood to adulthood. Major signs and symptoms include enlargement of the liver and spleen (hepatosplenomegaly), a low number of red blood cells (anemia), easy bruising caused by a decrease in blood platelets (thrombocytopenia), lung disease, and bone abnormalities such as bone pain, fractures, and arthritis.

**Types 2 and 3 Gaucher disease** are known as neuronopathic forms of the disorder because they are characterized by problems that affect the central nervous system. In addition to the signs and symptoms described above, these conditions can cause abnormal eye movements, seizures, and brain damage. Type 2 Gaucher disease usually causes life-threatening medical problems beginning in infancy. Type 3 Gaucher disease also affects the nervous system, but tends to progress more slowly than type 2.

The most severe type of Gaucher disease is called the perinatal lethal form. This condition causes severe or life-threatening complications starting before birth or in infancy. Features of the perinatal lethal form can include extensive swelling caused by fluid accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or other skin abnormalities; hepatosplenomegaly; distinctive facial features; and serious neurological problems. As its name indicates, most infants with the perinatal lethal form of Gaucher disease survive for only a few days after birth.

Another form of Gaucher disease is known as the cardiovascular type because it primarily affects the heart, causing the heart valves to harden (calcify). People with the cardiovascular form of Gaucher disease may also have eye abnormalities, bone disease, and mild enlargement of the spleen (splenomegaly).

**Gerstmann Syndrome**

Gerstmann-Straussler-Scheinker syndrome is a rare familial form of progressive dementia inherited in an autosomal dominant manner due to a mutant prion gene on chromosome 20pter-p12. Abbreviated GSS.

Degeneration of the nervous system usually starts in the fourth or fifth decade of life with slowly developing dysarthria (difficulty speaking) and cerebellar ataxia (wobbliness) and later the progressive dementia become evident. Death usually occurs within 10 years of the onset of symptoms.

The syndrome was first described in 1936 by the Austrian neurologists Josef Gerstmann (1887-1969), Ernst Sträussler (1872-1959), and I. Scheinker. The syndrome is now known to be a form of transmissible spongiform encephalopathy (TSE) - a prion disease.

Also called Gerstmann-Sträussler disease or syndrome, Gerstmann-Straussler disease or syndrome, Gerstmann-Straussler-Scheinker disease or syndrome, cerebral amyloidosis with spongiform encephalopathy, cerebellar ataxia with progressive dementia, subacute spongiform encephalopathy, and prion dementia.

**Giant Lymph Node Hyperplasia**

Castleman's disease (giant or angiofollicular lymph node hyperplasia, lymphoid hamartoma, angiofollicular lymph node hyperplasia) is an uncommon lymphoproliferative disorder that can involve single lymph node stations or can be systemic. It must be distinguished from reactive lymph node hyperplasia and malignancies.[1] It is a very rare disorder characterized by non-cancerous growths (tumors) that may develop in the lymph node tissue at a single site or throughout the body. [2] It involves hyperproliferation of certain B cells that often produce cytokines. While not officially considered a cancer, the overgrowth of lymphocytes with this disease is similar to lymphoma.[3]

There are several variants of Castleman's disease.

In most of the cases, Castleman's disease is likely due to hypersecretion of the cytokine IL-6,[6] but some patients may have normal IL-6 levels and present with non-iron-deficient microcytic anemia.[1]

In tumors that are positive for Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpes virus 8 (HHV-8), this is most likely due to expression of the virus-encoded cytokine, vIL-6.[7]

KSHV negative tumors appear to be the result of over-secretion of human IL-6.

Unicentric vs. multicentric

**Unicentric Castleman's disease** involves tissue growths at only a single site. It usually has few or no symptoms other than those directly associated with the physical enlargement of the lymph node. In 90% or more, removal of the enlarged node is curative, with no further complications. However, in 2011, Weng et al. described a patient with unicentric Castleman's disease, hyaline vascular type, presenting with severe chronic non-iron-deficient anemia. He suggested that in patients with normal IL-6 level may present with non-iron deficient type and may resolve after effective treatment of Castleman's disease.[1]

**Multicentric Castleman's disease** (MCD) involves growths at multiple sites.[8] About 50% is caused by KSHV, also called HHV-8, a gammaherpesvirus that is also the cause of Kaposi's sarcoma and primary effusion lymphoma, while the remainder of MCD are of unknown cause. The form of MCD most closely associated with KSHV is the plasmacytic form of Castleman's disease while another pathologic form, the hyaline-vascular form, is generally negative for this virus.

The most common 'B Symptoms' of MCD are high fevers, anemia, weight loss, loss of appetite, and low white blood cell counts, which may to be due to the overproduction of interleukin 6. Symptomatically, therefore, MCD can be difficult to diagnose and even in the case of a lymph-node biopsy a conclusive diagnosis remains problematic.

Castleman's is seen in POEMS syndrome and is implicated in 10% of cases of paraneoplastic pemphigus.

**Goldenhar Syndrome**

Goldenhar syndrome is congenital malformation of the jaw, cheek and ear associated with vertebral defects. There is deformity of the external ear and abnormal smallness of that half of the face. Coloboma (cleft) of the upper eyelid is frequent. The ear deformities range from tags in front of the ear, to atresia (closure) of the external auditory canal, abnormalities in the size and shape of the ear, and even anotia (lack of the ear). These features represent problems that occurred in the development of structures known as the first and second branchial archs during embryonic life. Most of the children with the disorder are of normal intelligence. Cosmetic surgery is needed. Other names for the condition include hemifacial microsomia, facio-auriculo-vertebral spectrum, facioauriculovertebral sequence, oculo-auriculo-vertebral spectrum, oculoauriculovertebral dysplasia, and the first and second branchial arch syndrome.

**Guillain-Barre Syndrome**

Guillain-Barré syndrome is a disorder in which the body's immune system attacks part of the peripheral nervous system. The first symptoms of this disorder include varying degrees of weakness or tingling sensations in the legs. In many instances the weakness and abnormal sensations spread to the arms and upper body. These symptoms can increase in intensity until certain muscles cannot be used at all and, when severe, the patient is almost totally paralyzed. In these cases the disorder is life threatening - potentially interfering with breathing and, at times, with blood pressure or heart rate - and is considered a medical emergency. Such a patient is often put on a respirator to assist with breathing and is watched closely for problems such as an abnormal heart beat, infections, blood clots, and high or low blood pressure. Most patients, however, recover from even the most severe cases of Guillain-Barré syndrome, although some continue to have a certain degree of weakness.

Guillain-Barré syndrome can affect anybody. It can strike at any age and both sexes are equally prone to the disorder. The syndrome is rare, however, afflicting only about one person in 100,000. Usually Guillain-Barré occurs a few days or weeks after the patient has had symptoms of a respiratory or gastrointestinal viral infection. Occasionally surgery or vaccinations will trigger the syndrome.

After the first clinical manifestations of the disease, the symptoms can progress over the course of hours, days, or weeks. Most people reach the stage of greatest weakness within the first 2 weeks after symptoms appear, and by the third week of the illness 90 percent of all patients are at their weakest.

No one yet knows why Guillain-Barré - which is not contagious - strikes some people and not others. Nor does anyone know exactly what sets the disease in motion.

What scientists do know is that the body's immune system begins to attack the body itself, causing what is known as an autoimmune disease. Usually the cells of the immune system attack only foreign material and invading organisms. In Guillain-Barré syndrome, however, the immune system starts to destroy the myelin sheath that surrounds the axons of many peripheral nerves, or even the axons themselves (axons are long, thin extensions of the nerve cells; they carry nerve signals). The myelin sheath surrounding the axon speeds up the transmission of nerve signals and allows the transmission of signals over long distances.

In diseases in which the peripheral nerves' myelin sheaths are injured or degraded, the nerves cannot transmit signals efficiently. That is why the muscles begin to lose their ability to respond to the brain's commands, commands that must be carried through the nerve network. The brain also receives fewer sensory signals from the rest of the body, resulting in an inability to feel textures, heat, pain, and other sensations. Alternately, the brain may receive inappropriate signals that result in tingling, "crawling-skin," or painful sensations. Because the signals to and from the arms and legs must travel the longest distances they are most vulnerable to interruption. Therefore, muscle weakness and tingling sensations usually first appear in the hands and feet and progress upwards.

When Guillain-Barré is preceded by a viral or bacterial infection, it is possible that the virus has changed the nature of cells in the nervous system so that the immune system treats them as foreign cells. It is also possible that the virus makes the immune system itself less discriminating about what cells it recognizes as its own, allowing some of the immune cells, such as certain kinds of lymphocytes and macrophages, to attack the myelin. Sensitized T lymphocytes cooperate with B lymphocytes to produce antibodies against components of the myelin sheath and may contribute to destruction of the myelin. Scientists are investigating these and other possibilities to find why the immune system goes awry in Guillain-Barré syndrome and other autoimmune diseases. The cause and course of Guillain-Barré syndrome is an active area of neurological investigation, incorporating the cooperative efforts of neurological scientists, immunologists, and virologists.

**Hallermann's Syndrome**

Hallermann-Streiff-François (HSF) syndrome is marked by a characteristic facies with hypoplastic mandible and beaked nose, proportionate short stature (2/3), hypotrichosis (80%), microphthalmia (80%) with congenital cataract (80-90%), hypodontia (80%), hypotrichosis (80%), skin atrophy of the face (70%) and hypoplasia of the clavicles and ribs. About 15% of cases display intellectual deficit. Neonatal teeth may be present. Less than 100 cases have been reported so far in the literature and the vast majority of cases are sporadic. The genetic basis is still unknown. Upper airway obstruction may result from small nares and glossoptosis (tongue falling backwards) secondary to micrognathia, and these may lead to cor pulmonale. Snoring and/or daytime hypersomnolence are indications for sleep studies. Tracheomalacia is a complication that can lead to chronic respiratory insufficiency, resulting in biventricular cardiac failure and early death. Severe and lethal forms of HSF exist, with slender long bones and underossified skull, but it is not clear whether they are the same disorder, as these lethal forms (referred to as osteocraniostenosis) are recessively inherited. Differential diagnosis should be made with the other forms of progeroid syndromes (Hutchinson-Gilford progeria, Werner syndrome, acromandibular dysplasia) and oculodentodigital dysplasia.

**Hallervorden-Spatz Syndrome**

Hallervorden-Spatz disease is a genetic disorder in which there is progressive neurologic degeneration with the accumulation of iron in the brain. The gene for the disease is on chromosome 20 in region 20p13-p12.3.

The syndrome was first described by Julius Hallervorden and Hugo Spatz in 1922 in 5 sisters who showed increasing dysarthria (trouble speaking) and progressive dementia and, at autopsy, brown discoloration of specific parts of the brain (the globus pallidus and substantia nigra).

The disease is characterized by progressive rigidity, first in the lower and later in the upper extremities. Involuntary movements of choreic or athetoid type may precede or accompany the rigidity. Both involuntary movements and rigidity may involve muscles supplied by cranial nerves, resulting in difficulties in articulation and swallowing. This disorder affects the muscular tone and voluntary movements progressively, making coordinated movements and chewing and swallowing almost impossible. Mental deterioration, emaciation, severe feeding difficulties, and visual impairment occur commonly in the late stages of the disease.

The disease has its onset in the first or second decade of life. The average survival time after the diagnosis is made 11 years. Death usually occurs before the age of 30 years.

The diagnosis of Hallervorden-Spatz disease has usually been made postmortem. However, magnetic resonance imaging (MRI) alterations in the basal ganglia of the brain now permit diagnosis during life in someone who has an affected sibling and is therefore at high (25%) risk for the disease.

Hallervorden whose name is associated with this disease made important contributions to neurology. However, his active involvement in euthanasia in Germany during World War II raises serious questions about the moral obligations of medical science. No euthanasia law was ever enacted in the Third Reich. Rather, physicians were empowered to carry out 'mercy killings' but were never obliged to do so. There was never a direct order to participate, and refusal to cooperate did not result in legal action or professional setback. Hallervorden's enthusiastically encouraged the killings and the other aspects that led to the dehumanization of both the victims and the participants. Some believe that Hallervorden's name should be removed from this disorder. It has been suggested that the disease might be called "Martha-Alma disease" for the 2 unfortunate sisters whose brains were first dissected in the original description of the disease by Hallervorden and Spatz.

Other names for this disorder include neurodegeneration with brain iron accumulation (NBIA) and late infantile neuroaxonal dystrophy.

**Hamartoma Syndrome, Multiple**

Cowden syndrome is an autosomal dominant disorder characterized by multiple hamartomas (occurring in the skin, breast, thyroid, gastrointestinal tract, endometrium and brain), and an increased risk of malignant tumors (breast, endometrial and thyroid cancer). Skin is involved in 90-100% of cases (trichilemmomas, oral mucosal papillomatosis, acral keratoses and palmoplantar keratoses). The exact prevalence is unknown, the estimated prevalence is 1 in 200,000. Cowden syndrome results most commonly from a mutation in the _PTEN_(phosphatase and tensin homolog) gene at locus 10q23.2. Management is aimed primarily at early detection of malignant conditions.

**Hartnup Disease**

Hartnup syndrome is a rare metabolic disorder belonging to the neutral aminoacidurias and characterized by abnormal renal and gastrointestinal transport of neutral amino acids (tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine and valine). The estimated prevalence is approximately 1 in 24,000. Clinical symptoms usually appear in childhood (3-9 years of age), but sometimes manifest as early as 10 days after birth, or as late as early adulthood. Most subjects remain asymptomatic. Symptomatic subjects usually present with skin photosensitivity (pellagra-like skin eruption), neurological symptoms (cerebellar ataxia, spasticity, delayed motor development, trembling, headaches, and hypotonia), psychiatric symptoms (anxiety, emotional instability, delusions, and hallucinations), and aminoaciduria. Ocular manifestations may occur (double vision, nystagmus, photophobia, and strabismus). Intellectual deficit and short stature have been described in a few patients. Exacerbations are seen most frequently in the spring or early summer after sunlight exposure. Symptoms may also be triggered by fever, drugs, and emotional or physical stress. They progress over several days and last for 1-4 weeks before spontaneous remission occurs. Hartnup syndrome is an autosomal recessive disorder caused by mutations in the_SLC6A19_ gene (5p15.33). _SLC6A19_ encodes a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in the kidneys and intestine. Treatment includes nicotinamide supplements (40 to 200 mg per day). Neutral hyperaminoaciduria (determined by urine chromatography) is the diagnostic hallmark. Pellagra is the main differential diagnosis. Blue diaper syndrome, ataxia-telangiectasia, hydroa vacciniforme, pityriasis alba, and xeroderma pigmentosum (see these terms) should be excluded. All patients benefit from a high-protein diet, sunlight protection, and avoidance of photosensitizing drugs. Some patients may respond to a tryptophan-rich diet. Patients with severe central nervous system involvement require neurologic and psychiatric treatment.

**Hepatic Vein Thrombosis**

Budd–Chiari syndrome(Hepatic Vein Thrombosis) is the clinical picture caused by occlusion of the hepatic veins. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. The syndrome can be fulminant, acute, chronic, or asymptomatic.

The acute syndrome presents with rapidly progressive severe upper abdominal pain, jaundice, hepatomegaly (enlarged liver), ascites, elevated liver enzymes, and eventually encephalopathy. The fulminant syndrome presents early with encephalopathy and ascites. Severe hepatic necrosis and lactic acidosis may be present as well. Caudate lobe hypertrophy is often present. The majority of patients have a slower-onset form of Budd–Chiari syndrome. This can be painless. A system of venous collaterals may form around the occlusion which may be seen on imaging as a "spider's web." Patients may progress to cirrhosis and show the signs of liver failure.

On the other hand, incidental finding of a silent, asymptomatic form may not be a cause for concern.

The cause cannot be found in about half of the patients

Primary (75%): thrombosis of the hepatic vein

Secondary (25%): compression of the hepatic vein by an outside structure (e.g. a tumor)

Hepatic vein thrombosis is associated with the following in decreasing order of frequency:  
a) Polycythemia vera  
b) pregnancy  
c) post partum state  
d) use of oral contraceptive  
e) paroxysmal nocturnal hemoglobinuria  
f) Hepatocellular carcinoma

Infection such as tuberculosis

Congenital venous webs

Occasionally inferior vena caval stenosis

Often, the patient is known to have a tendency towards thrombosis, although Budd–Chiari syndrome can also be the first symptom of such a tendency. Examples of genetic tendencies include Protein C deficiency, Protein S deficiency, the Factor V Leiden mutation, Hereditary anti-thrombin deficiency and Prothrombin Mutation G20210A.[1] An important non-genetic risk factor is the use of estrogen-containing (combined) forms of hormonal contraception. Other risk factors include the antiphospholipid syndrome, aspergillosis, Behçet's disease, dacarbazine, pregnancy, and trauma.

Many patients have Budd–Chiari syndrome as a complication of polycythemia vera (myeloproliferative disease of red blood cells).[2] Patients suffering from paroxysmal nocturnal hemoglobinuria(PNH) appear to be especially at risk for Budd–Chiari syndrome, more than other forms of thrombophilia: up to 39% develop venous thromboses [3] and 12% may acquire Budd-Chiari.[4]

A related condition is veno-occlusive disease, which occurs in recipients of bone marrow transplants as a complication of their medication. Although its mechanism is similar, it is not considered a form of Budd–Chiari syndrome.

Other toxicologic causes of veno-occlusive disease include plant & herbal sources of pyrrolizidine alkaloids such as Borage, Boneset, Coltsfoot, T'u-san-chi, Comfrey, Heliotrope (sunflower seeds), Gordolobo, Germander, and Chaparral.

Any obstruction of the venous vasculature of the liver is referred to as Budd–Chiari syndrome, from the venules to the right atrium. This leads to increased portal vein and hepatic sinusoid pressures as the blood flow stagnates. The increased portal pressure causes: 1) increased filtration of vascular fluid with the formation of ascites in the abdomen; and 2) collateral venous flow through alternative veins leading to esophageal, gastric and rectal varices. Obstruction also causes centrilobular necrosis and peripheral lobule fatty change due to ischemia. If this condition persists chronically what is known as Nutmeg liver will develop. Renal failure may occur, perhaps due to the body sensing an "underfill" state and subsequent activation of the renin-angiotensin pathways and excess sodium retention.

Several studies have attempted to predict the survival of patients with Budd–Chiari syndrome. In general, nearly 2/3 of patients with Budd-Chiari are alive at 10 years. [5] Important negative prognostic indicators include ascites, encephalopathy, elevated Child-Pugh scores, elevated prothrombin time, and altered serum levels of various substances (sodium, creatinine, albumin, and bilirubin). Survival is also highly dependent on the underlying cause of the Budd–Chiari syndrome. For example, a patient with an underlying myeloproliferative disorder may progress to acute leukemia, independently of Budd–Chiari syndrome.

**Hepatolenticular Degeneration**

Wilson disease is an autosomal recessive disorder characterised by the toxic accumulation of copper, mainly in the liver and central nervous system. It is a rare disease with an estimated incidence in France of between 1/30 000 and 1/100 000 new cases per year. The prevalence is estimated at 1 in 25 000. Symptomatic patients may present with hepatic, neurologic or psychiatric forms. Diagnosis depends the clinical and phenotypic evidence for the disease and on the detection of the associated genetic anomalies. The disease results from mutations in the _ATP7B_ gene on chromosome 13. The discovery of the gene has led to a better understanding of cytosolic copper trafficking and its relationship with ceruloplasmin synthesis. This disease can be efficiently treated by chelation and zinc therapy. Liver transplantation is the recommended therapy for patients with fulminant hepatitis, or in those with relentless progression of hepatic dysfunction despite drug therapy.

**Hereditary Motor and Sensory Neuropathies**

Hereditary motor and sensory neuropathies (HMSN) are a group of neuropathies which are characterized by their impact upon both afferent and efferent neural communication.

They are more common than hereditary sensory and autonomic neuropathies.[1]

There are six types of HMSN.

The first, second, fifth, and sixth type, Charcot–Marie–Tooth disease (CMT), also known as Charcot–Marie–Toothneuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA) — is a genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterised by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is one of the most common inherited neurological disorders affecting approximately 1 in 2,500 people [1][2] equating to approximately 23,000 people in the United Kingdom and 125,000 people in the USA.

CMT was previously classified as a subtype of muscular dystrophy.[1]

Symptoms of CMT usually begin in late childhood or early adulthood. Some people do not experience symptoms until their early thirties or forties. Usually, the initial symptom is foot drop early in the course of the disease. This can also cause claw toe, where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted bottle" appearance. Weakness in the hands and forearms occurs in many people later in life as the disease progresses.

Loss of touch sensation in the feet, ankles and legs, as well as in the hands, wrists and arms is characteristic in various types of the disease. Early and late onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates. High arched feet (pes cavus) are classically associated with the disorder. Sensory and proprioceptive nerves in the hands and feet are often damaged, while pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping.

Symptoms and progression of the disease can vary. Breathing can be affected in some; so can hearing, vision, as well as the neck and shoulder muscles. Scoliosis is common. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT, as can chewing, swallowing, and speaking (due to atrophy of vocal cords). A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as extreme emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from a secondary injury as prolonged periods of limited mobility can drastically accelerate symptoms of CMT.[3]

Neuropathic pain is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity varies from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When pain is present as a symptom of CMT, it is comparable to that seen in other peripheral neuropathies, as well as Postherpetic neuralgia and Complex regional pain syndrome, among other diseases.[4]

Charcot–Marie–Tooth disease is caused by mutations that cause defects in neuronal proteins. Nerve signals are conducted by an axon with a myelin sheath wrapped around it. Most mutations in CMT affect the myelin sheath, but some affect the axon.

The most common cause of CMT (70-80% of the cases) is the duplication of a large region in chromosome 17p12 that includes the gene PMP22. Some mutations affect the gene MFN2, which codes for a mitochondrial protein. Cells contain separate sets of genes in their nucleus and in their mitochondria. In nerve cells, the mitochondria travel down the long axons. In some forms of CMT, mutated MFN2 causes the mitochondria to form large clusters, or clots, which are unable to travel down the axon towards the synapses. This prevents the synapses from functioning.[5]

CMT is divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2), with frequent overlap. Another cell involved in CMT is the Schwann cell, which creates the myelin sheath, by wrapping its plasma membrane around the axon in a structure that is sometimes compared to a Swiss roll.[6]

Neurons, Schwann cells, and fibroblasts work together to create a working nerve. Schwann cells and neurons exchange molecular signals that regulate survival and differentiation. These signals are disrupted in CMT.[6]

Demyelinating Schwann cells causes abnormal axon structure and function. They may cause axon degeneration, or they may simply cause axons to malfunction.[1]

The myelin sheath allows nerve cells to conduct signals faster. When the _myelin sheath_ is damaged, nerve signals are slower, and this can be measured by a common neurological test, electromyography. When the _axon_ is damaged, on the other hand, this results in a reduced compound muscle action potential (CMAP).[7]

The third type is Dejerine–Sottas disease, also Dejerine–Sottas syndrome or Dejerine–Sottas neuropathy (hereditary motor and sensory polyneuropathy type III; sometimes also described as a subtype III of Charcot–Marie–Tooth disease) is an autosomal dominant or autosomal recessive neuropathy, which causes damage to the peripheral nerves.[1]

Dejerine-Sottas Disease is caused by a genetic defect either in the proteins found in axons or the proteins found in myelin. It can be either an autosomal dominant or autosomal recessive neuropathy.[1] Specifically, it has been associated with MPZ,[4] PMP22,[5] PRX,[6] and EGR2.[7]

Onset occurs in infancy or early childhood, usually before 3 years of age. Progression is slow until the teenage years at which point it may accelerate, resulting in severe disability.

Symptoms are usually more severe and rapidly progressive than in the other more common Charcot–Marie–Tooth diseases. Some carriers may never walk and solely use wheelchairs by the end of their first decade, while others may need only a cane (walking stick) or similar support through life.

Dejerine-Sottas Disease is characterized by moderate to severe lower and upper extremity weakness and loss of sensation, which occur mainly in the lower legs, forearms, feet and hands. Loss of muscle mass and reduced muscle tone can occur as the disease progresses. Other symptoms may include pain in the extremities, curvature of the spine, clawed hands, foot deformities, ataxia, peripheral areflexia, and slow acquisition of motor skills in childhood. Symptoms that are less common can include limitation of eye movements, other eye problems such as nystagmus or anisocoria, or mild hearing loss.

Type four is Refsum disease, also known as classic or adult Refsum disease, heredopathia atactica polyneuritiformis, phytanic acid oxidase deficiency and phytanic acid storage disease,[1][2][3][4] is an autosomal recessive[5] neurologicl disease that results from the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991).[6][7]

Adult Refsum disease may be divided into the adult Refsum disease 1 and adult Refsum disease 2 subtypes. The former stems from mutations in the phytanoyl-CoA hydroxylase (_PAHX_ aka_PHYH_) gene, while the latter stems from mutations in the peroxin 7 (_PEX7_) gene.[1]

Adult Refsum disease should not be confused with infantile Refsum disease, a peroxisome biogenesis disorder resulting from deficiencies in the catabolism of very long chain fatty acids and branched chain fatty acids (such as phytanic acid) and plasmalogen biosynthesis.[1][8]

Individuals with Refsum disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy. Onset is most commonly in childhood/adolescence with a progressive course, although periods of stagnation or remission occur. Symptoms also include ataxia, scaly skin (ichthyosis), difficulty hearing, and eye problems including cataracts and night blindness.

Refsum disease is a peroxisomal disorder caused by the impaired alpha-oxidation of branched chain fatty acids resulting in buildup of phytanic acid and its derivatives in the plasma and tissues. This may be due to deficiencies of phytanoyl-CoA hydroxylase or peroxin-7 activity. In general, Refsum disease is caused by _PHYH_ mutations.

In ruminant animals, the gut fermentation of consumed plant materials liberates phytol, a constituent of chlorophyll, which is then converted to phytanic acid and stored in fats.[12] Although humans cannot derive significant amounts of phytanic acid from the consumption of chlorophyll present in plant materials, it has been proposed that the great apes (bonobos, chimpanzees, gorillas, and orangutans) can derive significant amounts of phytanic acid from the hindgut fermentation of plant materials.[13]

The seventh type, Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes severe vision impairment and often blindness.[1] Sufferers will experience one or more of the following symptoms:

Night blindness or nyctalopia;

Tunnel vision (no peripheral vision);

Peripheral vision (no central vision);

Latticework vision;

Aversion to glare;

Slow adjustment from dark to light environments and vice versa;

Blurring of vision;

Poor color separation; and

Extreme tiredness.

The progress of RP is not consistent. Some people will exhibit symptoms from infancy, others may not notice symptoms until later in life.[2] Generally, the later the onset, the more rapid is the deterioration in sight. Also notice that people who do not have RP have 90 degree peripheral vision, while some people that have RP have less than 90 degree.

A form of retinal dystrophy, RP is caused by abnormalities of the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) of the retina leading to progressive sight loss. Affected individuals may experience defective light to dark, dark to light adaptation or nyctalopia (night blindness), as the result of the degeneration of the peripheral visual field (known as tunnel vision). Sometimes, central vision is lost first causing the person to look sidelong at objects.

The effect of RP is best illustrated by comparison to a television or computer screen. The pixels of light that form the image on the screen equate to the millions of light receptors on the retina of the eye. The fewer pixels on a screen, the less distinct will be the images it will display. Fewer than 10 percent of the light receptors in the eye receive the colored, high intensity light seen in bright light or daylight conditions. These receptors are located in the center of the circular retina. The remaining 90 percent of light receptors receive gray-scale, low intensity light used for low light and night vision and are located around the periphery of the retina. RP destroys light receptors from the outside inward, from the center outward, or in sporadic patches with a corresponding reduction in the efficiency of the eye to detect light. This degeneration is progressive and has no known cure as of June 2012.

The most challenging aspect of RP is that it is not stable. Sufferers must continually adapt to less and less sight and how that impacts their life, career and relationships. Another aspect is that RP sufferers do not look different. RP does not result in any outward effect on the eyes and so people with RP "do not look blind". Furthermore, though legally blind because of reduced field of vision or acuity, they may be able to see things that hold in their line of sight long enough (if bright enough) to comprehend e.g. see large or bright objects albeit indistinctly.

Mottling of the retinal pigment epithelium with black bone-spicule pigmentation is typically indicative (or pathognomonic) of retinitis pigmentosa. Other ocular features include waxy pallor of the optic nerve head, attenuation (thinning) of the retinal vessels, cellophane maculopathy, cystic macular edema and posterior subcapsular cataract.

The diagnosis of retinitis pigmentosa relies upon documentation of progressive loss in photoreceptor cell function by electroretinography (ERG) and visual field testing.

The mode of inheritance of RP is determined by family history. At least 35 different genes or loci are known to cause "nonsyndromic RP" (RP that is not the result of another disease or part of a wider syndrome).

DNA testing is available on a clinical basis for:

_RLBP1_ (autosomal recessive, Bothnia type RP)

_RP1_ (autosomal dominant, RP1)

_RHO_ (autosomal dominant, RP4)

_RDS_ (autosomal dominant, RP7)

_PRPF8_ (autosomal dominant, RP13)

_PRPF3_ (autosomal dominant, RP18)

CRB1 (autosomal recessive, RP12)

_ABCA4_ (autosomal recessive, RP19)

_RPE65_ (autosomal recessive, RP20)

For all other genes (e.g. DHDDS), molecular genetic testing is available on a research basis only.

RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. X-linked RP can be either recessive, affecting primarily only males, or dominant, affecting both males and females, although males are usually more mildly affected. Some digenic (controlled by two genes) and mitochondrial forms have also been described.

Genetic counseling depends on an accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing.

Retinitis pigmentosa (RP) is seen in a variety of diseases, so the differential of this sign alone is broad.

RP combined with deafness (congenital or progressive) is called Usher syndrome.

RP combined with opthalmoplegia, dysphagia, ataxia, and cardiac conduction defects is seen in the mitochondrial DNA disorder Kearns-Sayre syndrome (also known as Ragged Red FiberMyopathy)

RP combined with retardation, peripheral neuropathy, acanthotic (spiked) RBCs, ataxia, steatorrhea, is absence of VLDL is seen in abetalipoproteinemia.

RP is seen clinically in association with several other rare genetic disorders (including muscular dystrophy and chronic granulomatous disease) as part of McLeod syndrome. This is an X-linked recessive phenotype characterized by a complete absence of XK cell surface proteins, and therefore markedly reduced expression of all Kell red blood cell antigens. For transfusion purposes these patients are considered completely incompatible with all normal and K0/K0 donors.

Other conditions include neurosyphilis, toxoplasmosis(Emedicine "Retinitis Pigmentosa") and Refsum's disease.

Retinitis pigmentosa (RP) is one of the most common forms of inherited retinal degeneration.[3] This disorder is characterized by the progressive loss of photoreceptor cells and may eventually lead to blindness.[4]

There are multiple genes that, when mutated, can cause the Retinitis pigmentosa phenotype.[5] In 1989, a mutation of the gene for rhodopsin, a pigment that plays an essential part in the visual transduction cascade enabling vision in low-light conditions, was identified. Since then, more than 100 mutations have been found in this gene, accounting for 15% of all types of retinal degeneration. Most of those mutations are missense mutations and inherited mostly in a dominant manner.

Types include:

**OMIM**

**Gene**

**Type**

180100

RP1

Retinitis pigmentosa-1

312600

RP2

Retinitis pigmentosa-2

300029

RPGR

Retinitis pigmentosa-3

608133

PRPH2

Retinitis pigmentosa-7

180104

RP9

Retinitis pigmentosa-9

180105

IMPDH1

Retinitis pigmentosa-10

600138

PRPF31

Retinitis pigmentosa-11

600105

CRB1

Retinitis pigmentosa-12, autosomal recessive

600059

PRPF8

Retinitis pigmentosa-13

600132

TULP1

Retinitis pigmentosa-14

600852

CA4

Retinitis pigmentosa-17

601414

HPRPF3

Retinitis pigmentosa-18

601718

ABCA4

Retinitis pigmentosa-19

602772

EYS

Retinitis pigmentosa-25

608380

CERKL

Retinitis pigmentosa-26

607921

FSCN2

Retinitis pigmentosa-30

609923

TOPORS

Retinitis pigmentosa-31

610359

SNRNP200

Retinitis pigmentosa 33

610282

SEMA4A

Retinitis pigmentosa-35

610599

PRCD

Retinitis pigmentosa-36

611131

NR2E3

Retinitis pigmentosa-37

268000

MERTK

Retinitis pigmentosa-38

268000

USH2A

Retinitis pigmentosa-39

612095

PROM1

Retinitis pigmentosa-41

612943

KLHL7

Retinitis pigmentosa-42

268000

CNGB1

Retinitis pigmentosa-45

613194

BEST1

Retinitis pigmentosa-50

613464

TTC8

Retinitis pigmentosa 51

613428

C2orf71

Retinitis pigmentosa 54

613575

ARL6

Retinitis pigmentosa 55

613617

ZNF513

Retinitis pigmentosa 58

613861

DHDDS

Retinitis pigmentosa 59

613194

BEST1

Retinitis pigmentosa, concentric

608133

PRPH2

Retinitis pigmentosa, digenic

613341

LRAT

Retinitis pigmentosa, juvenile

268000

SPATA7

Retinitis pigmentosa, juvenile, autosomal recessive

268000

CRX

Retinitis pigmentosa, late-onset dominant

300455

RPGR

Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness

The rhodopsin gene encodes a principal protein of photoreceptor outer segments. Studies show that mutations in this gene are responsible for approximately 25% of autosomal dominan forms of RP.[3][6]

Mutations in four pre-mRNA splicing factors are known to cause autosomal dominant retinitis pigmentosa. These are PRPF3 (human PRPF3 is HPRPF3; also PRP3), PRPF8, PRPF31 andPAP1. These factors are ubiquitously expressed and it is proposed that defects in a ubiquitous factor (a protein expressed everywhere) should only cause disease in the retina because the retinal photoreceptor cells have a far greater requirement for protein processing (rhodopsin) than any other cell type.[7]

Up to 150 mutations have been reported to date in the opsin gene associated with the RP since the Pro23His mutation in the intradiscal domain of the protein was first reported in 1990. These mutations are found throughout the opsin gene and are distributed along the three domains of the protein (the intradiscal, transmembrane, and cytoplasmic domains). One of the main biochemical causes of RP in the case of rhodopsin mutations is protein misfolding, and molecular chaperones have also been involved in RP.[8] It was found that the mutation of codon 23 in the rhodopsin gene, in which proline is changed to histidine, accounts for the largest fraction of rhodopsin mutations in the United States. Several other studies have reported other mutations which also correlate with the disease. These mutations include Thr58Arg, Pro347Leu, Pro347Ser, as well as deletion of Ile-255.[6][9][10][11][12] In 2000, a rare mutation in codon 23 was reported causing autosomal dominant retinitis pigmentosa, in which proline changed to alanine. However, this study showed that the retinal dystrophy associated with this mutation was characteristically mild in presentation and course. Furthermore, there was greater preservation in electroretinography amplitudes than the more prevalent Pro23His mutation.[13]

**Hirschsprung Disease**

Hirschsprung* disease (HD) is a disease of the large intestine that causes severe constipation or intestinal obstruction. Constipation means stool moves through the intestines slower than usual. Bowel movements occur less often than normal and stools are difficult to pass. Some children with Hirschsprung disease can't pass stool at all, which can result in the complete blockage of the intestines, a condition called intestinal obstruction. People with Hirschsprung disease are born with it and are usually diagnosed when they are infants. Less severe cases are sometimes diagnosed when a child is older. An Hirschsprung disease diagnosis in an adult is rare.

The large intestine, which includes the colon and rectum, is the last part of the digestive tract. The large intestine's main job is to absorb water and hold stool. The rectum connects the colon to the anus. Stool passes out of the body through the anus. At birth, the large intestine is about 2 feet long. An adult's large intestine is about 5 feet long.

People with Hirschsprung disease have constipation because they lack nerve cells in a part or all of the large intestine. The nerve cells signal muscles in the large intestine to push stool toward the anus. Without a signal to push stool along, stool will remain in the large intestine.

In a healthy large intestine the nerve cells are found throughout the large intestine.

Short-segment Hirschsprung disease. Nerve cells are missing from the last segment of the large intestine.

Long-segment Hirschsprung disease. Nerve cells are missing from most or all of the large intestine and sometimes the last part of the small intestine.

How severe Hirschsprung disease is depends on how much of the large intestine is affected. Short-segment Hirschsprung disease means only the last part of the large intestine lacks nerve cells. Long-segment Hirschsprung disease means most or all of the large intestine, and sometimes the last part of the small intestine, lacks nerve cells.

In a person with Hirschsprung disease, stool moves through the large intestine until it reaches the part lacking nerve cells. At that point, the stool moves slowly or stops, causing an intestinal obstruction.

Before birth, a child's nerve cells normally grow along the intestines in the direction of the anus. With Hirschsprung disease, the nerve cells stop growing too soon. Why the nerve cells stop growing is unclear. Some Hirschsprung disease is inherited, meaning it is passed from parent to child through genes. Hirschsprung disease is not caused by anything a mother did while pregnant.

The main symptoms of Hirschsprung disease are constipation or intestinal obstruction, usually appearing shortly after birth. Constipation in infants and children is common and usually comes and goes, but if your child has had ongoing constipation since birth, Hirschsprung disease may be the problem.

Newborns with Hirschsprung disease almost always fail to have their first bowel movement within 48 hours after birth. Other symptoms include

green or brown vomit

explosive stools after a doctor inserts a finger into the rectum

swelling of the belly, also known as the abdomen

lots of gas

bloody diarrhea

Symptoms of Hirschsprung disease in toddlers and older children include

not being able to pass stools without laxatives or enemas. A laxative is medicine that loosens stool and increases bowel movements. An enema is performed by flushing water, or sometimes a mild soap solution, into the anus using a special wash bottle

swelling of the abdomen

lots of gas

bloody diarrhea

slow growth or development

lack of energy because of a shortage of red blood cells, called anemia.

**Histiocytic Necrotizing Lymphadenitis**

Histiocytic necrotizing lymphadenitis is a disorder, also called Kikuchi disease, that typically causes "swollen glands" in the neck (cervical lymphadeniopathy) together with fever or flu-like symptoms. Laboratory test abnormalities include elevated erythrocyte sedimentation rate (ESR), and white blood count abnormalities (low neutrophil count and elevated lymphocyte count with atypical lymphocytes in the peripheral blood).

Kikuchi disease is fairly common in young people, predominantly young women, in Asia. Also called Kikuchi-Fujimoto disease, this condition was discovered in Japan in 1972 and since then has seen in other areas of the world.

The overall picture is suggestive of a virus infection; autoimmune factors may also play a role. However, no infectious agent has yet been identified and autoimmunity remains hypothetical.

Diagnosis is based on characteristic pathologic findings on biopsy that differentiate this disease from others such as lymphoma, systemic lupus erythematosus, and infectious lymphadenopathies.

**Histiocytosis, Langerhans-Cell**

Langerhans cell histiocytosis (LCH) is a systemic disease associated with the proliferation and accumulation (usually in granulomas) of Langerhans cells in various tissues. Its prevalence is estimated at 1-2/100,000. In the majority of cases, onset occurs during childhood. Bone is the most frequently affected organ (80% of cases), followed by the skin (35% of cases) and then the pituitary gland (25% of cases). However, involvement of these organs does not affect the vital prognosis. Involvement of the haematopoietic system (cytopenia), lungs and liver is much less common (15-20% of cases) but results in more severe disease. The aggressive nature of the haematological forms in young children, the long-term sequelae associated with lung and liver (sclerosing cholangitis) involvement, and the neurodegenerative manifestations (2% of cases) make LCH a severe disease. The disease may occur as one or several crises. It may result in aesthetic or functional sequelae with variable expression depending on the sites involved (deafness, respiratory or hepatic failure, diabetes insipidus, growth hormone deficiency, and cerebellar syndrome). In adults, the clinical picture is characterised by isolated lung disease, with a strong association with smoking. Although progress has been made in understanding the pathology of the disease, the aetiology remains unknown. Diagnosis of LCH usually relies on histological and immunohistochemical analysis of the affected tissues. A thoracic CT scan showing typical radiological findings may allow diagnosis in adults with isolated lung involvement. A large range of alternative diagnoses may be considered, depending on the associated clinical picture and radiological findings. The choice of therapeutic approach depends on the extent of disease, determined by routine examinations (clinical examination, haemogram, liver function tests, and bone and chest radiographs). Local treatment is usually effective for forms limited to one organ. In children, treatment of the systemic forms relies on the combination of corticosteroids and vinblastine. Smoking cessation is necessary for adults with lung involvement. Second-line treatments are available in specialised centres for patients with progressive disease. Given the polymorphic and chronic nature of the disease, management of LCH should be multidisciplinary. Treatment protocols for adult forms of the disease are less well established than those for patients with childhood onset. Long-term follow-up is needed for detection and management of later-onset sequelae. The vital prognosis is not usually affected in childhood forms, except in cases with haematological involvement resistant to first-line therapies.

**Histiocytosis, Sinus**

Rosai–Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy, is a rare disorder of unknown etiology that is characterized by abundant histiocytes in the lymph nodes throughout the body.[1]:747

Lymphadenopathy of the neck is the most common place of histiocyte accumulation, although accumulation outside of lymph nodes may occur, as well. The most common sites of accumulation outside of the lymph nodes are skin, upper respiratory tract, and the sinuses.[2][3]

The symptoms of this disease vary with the site of accumulation similar to other regional tumors. For instance, accumulation in closed spaces such as the cranium can lead to poor outcomes compared to growth in the dermis of an extremity where surgical excision is possible.

**Hodgkin Disease**

Hodgkin lymphoma is a cancer that begins in cells of the immune system. The immune system fights infections and other diseases.

The lymphatic system is part of the immune system. The lymphatic system includes the following:

Lymph vessels: The lymphatic system has a network of lymph vessels. Lymph vessels branch into all the tissues of the body.

Lymph: The lymph vessels carry clear fluid called lymph. Lymph contains white blood cells, especially lymphocytes such as B cells and T cells.

Lymph nodes: Lymph vessels are connected to small, round masses of tissue called lymph nodes. Groups of lymph nodes are found in the neck, underarms, chest, abdomen, and groin. Lymph nodes store white blood cells. They trap and remove bacteria or other harmful substances that may be in the lymph.

Other parts of the lymphatic system: Other parts of the lymphatic system include the tonsils, thymus, and spleen. Lymphatic tissue is also found in other parts of the body including the stomach, skin, and small intestine.

Because lymphatic tissue is in many parts of the body, Hodgkin lymphoma can start almost anywhere. Usually, it's first found in a lymph node above the diaphragm, the thin muscle that separates the chest from the abdomen. But Hodgkin lymphoma also may be found in a group of lymph nodes. Sometimes it starts in other parts of the lymphatic system.

Hodgkin lymphoma begins when a lymphocyte (usually a B cell) becomes abnormal. The abnormal cell is called a Reed-Sternberg cell. (See photo below.)

The Reed-Sternberg cell divides to make copies of itself. The new cells divide again and again, making more and more abnormal cells. The abnormal cells don't die when they should. They don't protect the body from infections or other diseases. The buildup of extra cells often forms a mass of tissue called a growth or tumor.

Doctors seldom know why one person develops Hodgkin lymphoma and another does not. But research shows that certain risk factors increase the chance that a person will develop this disease.

The risk factors for Hodgkin lymphoma include the following:

**Certain viruses**: Having an infection with the Epstein-Barr virus (EBV) or the human immunodeficiency virus (HIV) may increase the risk of developing Hodgkin lymphoma. However, lymphoma is not contagious. You can't catch lymphoma from another person.

**Weakened immune system**: The risk of developing Hodgkin lymphoma may be increased by having a weakened immune system (such as from an inherited condition or certain drugs used after an organ transplant).

**Age**: Hodgkin lymphoma is most common among teens and adults aged 15 to 35 years and adults aged 55 years and older.

**Family history**: Family members, especially brothers and sisters, of a person with Hodgkin lymphoma or other lymphomas may have an increased chance of developing this disease.

Having one or more risk factors does not mean that a person will develop Hodgkin lymphoma. Most people who have risk factors never develop cancer.

Hodgkin lymphoma can cause many symptoms:

Swollen lymph nodes (that do not hurt) in the neck, underarms, or groin

Becoming more sensitive to the effects of alcohol or having painful lymph nodes after drinking alcohol

Weight loss for no known reason

Fever that does not go away

Soaking night sweats

Itchy skin

Coughing, trouble breathing, or chest pain

Weakness and tiredness that don't go away

Most often, these symptoms are not due to cancer. Infections or other health problems may also cause these symptoms. Anyone with symptoms that last more than 2 weeks should see a doctor so that problems can be diagnosed and treated.

*Hodgkin's lymphoma facts medical author: Melissa Conrad Stöppler, MD

Hodgkin's lymphoma is a type of lymphoma (cancer of the lymphatic system).

The most common symptom of Hodgkin's lymphoma is a painless swelling in the lymph nodes in the neck, underarm, or groin.

Some of those affected have other symptoms like fever, night sweats, fatigue, itching, or weakness.

Hodgkin's lymphoma is most common among teens and adults aged 15 to 35 years and adults aged 55 years and older.

Risk factors may include a weakened immune system, HIV or EBV infection, and a family history of the disease.

Hodgkin's lymphoma is diagnosed when abnormal tissue is detected by a pathologist after a biopsy of an enlarged lymph node.

The abnormal cells in Hodgkin's lymphoma are called Reed-Sternberg cells.

Staging of Hodgkin's lymphoma refers to the extent of spread of the abnormal cells within the body.

Imaging studies such as CT scanning, MRI, or PET scanning may be done to determine the stage of Hodgkin's lymphoma.

Treatment of Hodgkin's lymphoma depends on the symptoms, stage and location of disease, as well as the age and health of the patient.

Treatment of Hodgkin's lymphoma usually includes radiation therapy or chemotherapy.

Regular follow-up examinations are important after treatment for Hodgkin's lymphoma. Patients treated for Hodgkin's lymphoma have an increased risk of developing other types of cancer later in life, especially leukemia.

**Horner Syndrome**

Syndrome, Horner is a complex of abnormal findings, namely sinking in of one eyeball, ipsilateral ptosis (drooping of the upper eyelid on the same side) and miosis (constriction of the pupil of that eye) together with anhidrosis (lack of sweating) and flushing of the affected side of the face. Due to paralysis of certain nerves (specifically, the cervical sympathetic nerves). Also called Horner-Bernard syndrome, Bernard syndrome, Bernard-Horner syndrome and Horner's ptosis but far and away best known as Horner syndrome.

**Huntington Disease**

In 1872, the American physician George Huntington wrote about an illness that he called "an heirloom from generations away back in the dim past." He was not the first to describe the disorder, which has been traced back to the Middle Ages at least. One of its earliest names was chorea,* which, as in "choreography," is the Greek word for dance. The term chorea describes how people affected with the disorder writhe, twist, and turn in a constant, uncontrollable dance-like motion. Later, other descriptive names evolved. "Hereditary chorea" emphasizes how the disease is passed from parent to child. "Chronic progressive chorea" stresses how symptoms of the disease worsen over time. Today, physicians commonly use the simple term Huntington's disease (HD) to describe this highly complex disorder that causes untold suffering for thousands of families.

More than 15,000 Americans have HD. At least 150,000 others have a 50 percent risk of developing the disease and thousands more of their relatives live with the possibility that they, too, might develop HD.

Until recently, scientists understood very little about HD and could only watch as the disease continued to pass from generation to generation. Families saw the disease destroy their loved ones' ability to feel, think, and move. In the last several years, scientists working with support from the National Institute of Neurological Disorders and Stroke (NINDS) have made several breakthroughs in the area of HD research. With these advances, our understanding of the disease continues to improve.

This brochure presents information about HD, and about current research progress, to health professionals, scientists, caregivers, and, most important, to those already too familiar with the disorder: the many families who are affected by HD.

HD results from genetically programmed degeneration of nerve cells, called neurons,* in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. Specifically affected are cells of the basal ganglia, structures deep within the brain that have many important functions, including coordinating movement. Within the basal ganglia, HD especially targets neurons of the striatum, particularly those in the caudate nuclei and the pallidum. Also affected is the brain's outer surface, or cortex, which controls thought, perception, and memory.

HD is found in every country of the world. It is a familial disease, passed from parent to child through a mutation or misspelling in the normal gene.

A single abnormal gene, the basic biological unit of heredity, produces HD. Genes are composed of deoxyribonucleic acid (DNA), a molecule shaped like a spiral ladder. Each rung of this ladder is composed of two paired chemicals called bases. There are four types of bases-adenine, thymine, cytosine, and guanine-each abbreviated by the first letter of its name: A, T, C, and G. Certain bases always "pair" together, and different combinations of base pairs join to form coded messages. A gene is a long string of this DNA in various combinations of A, T, C, and G. These unique combinations determine the gene's function, much like letters join together to form words. Each person has about 30,000 genes-a billion base pairs of DNA or bits of information repeated in the nuclei of human cells-which determine individual characteristics or traits.

Genes are arranged in precise locations along 23 rod-like pairs of chromosomes. One chromosome from each pair comes from an individual's mother, the other from the father. Each half of a chromosome pair is similar to the other, except for one pair, which determines the sex of the individual. This pair has two X chromosomes in females and one X and one Y chromosome in males. The gene that produces HD lies on chromosome 4, one of the 22 non-sex-linked, or "autosomal," pairs of chromosomes, placing men and women at equal risk of acquiring the disease.

The impact of a gene depends partly on whether it is dominant or recessive. If a gene is dominant, then only one of the paired chromosomes is required to produce its called-for effect. If the gene is recessive, both parents must provide chromosomal copies for the trait to be present. HD is called an autosomal dominant disorder because only one copy of the defective gene, inherited from one parent, is necessary to produce the disease.

The genetic defect responsible for HD is a small sequence of DNA on chromosome 4 in which several base pairs are repeated many, many times. The normal gene has three DNA bases, composed of the sequence CAG. In people with HD, the sequence abnormally repeats itself dozens of times. Over time-and with each successive generation-the number of CAG repeats may expand further.

Each parent has two copies of every chromosome but gives only one copy to each child. Each child of an HD parent has a 50-50 chance of inheriting the HD gene. If a child does not inherit the HD gene, he or she will not develop the disease and cannot pass it to subsequent generations. A person who inherits the HD gene, and survives long enough, will sooner or later develop the disease. In some families, all the children may inherit the HD gene; in others, none do. Whether one child inherits the gene has no bearing on whether others will or will not share the same fate.

A small number of cases of HD are sporadic, that is, they occur even though there is no family history of the disorder. These cases are thought to be caused by a new genetic mutation-an alteration in the gene that occurs during sperm development and that brings the number of CAG repeats into the range that causes disease.

Early signs of the disease vary greatly from person to person. A common observation is that the earlier the symptoms appear, the faster the disease progresses.

Family members may first notice that the individual experiences mood swings or becomes uncharacteristically irritable, apathetic, passive, depressed, or angry. These symptoms may lessen as the disease progresses or, in some individuals, may continue and include hostile outbursts or deep bouts of depression.

HD may affect the individual's judgment, memory, and other cognitive functions. Early signs might include having trouble driving, learning new things, remembering a fact, answering a question, or making a decision. Some may even display changes in handwriting. As the disease progresses, concentration on intellectual tasks becomes increasingly difficult.

In some individuals, the disease may begin with uncontrolled movements in the fingers, feet, face, or trunk. These movements-which are signs of chorea-often intensify when the person is anxious. HD can also begin with mild clumsiness or problems with balance. Some people develop choreic movements later, after the disease has progressed. They may stumble or appear uncoordinated. Chorea often creates serious problems with walking, increasing the likelihood of falls.

The disease can reach the point where speech is slurred and vital functions, such as swallowing, eating, speaking, and especially walking, continue to decline. Some individuals cannot recognize other family members. Many, however, remain aware of their environment and are able to express emotions.

Some physicians have employed a recently developed Unified HD Rating Scale, or UHDRS, to assess the clinical features, stages, and course of HD. In general, the duration of the illness ranges from 10 to 30 years. The most common causes of death are infection (most often pneumonia), injuries related to a fall, or other complications.

The rate of disease progression and the age at onset vary from person to person. Adult-onset HD, with its disabling, uncontrolled movements, most often begins in middle age. There are, however, other variations of HD distinguished not just by age at onset but by a distinct array of symptoms. For example, some persons develop the disease as adults, but without chorea. They may appear rigid and move very little, or not at all, a condition called akinesia.

Some individuals develop symptoms of HD when they are very young-before age 20. The terms "early-onset" or "juvenile" HD are often used to describe HD that appears in a young person. A common sign of HD in a younger individual is a rapid decline in school performance. Symptoms can also include subtle changes in handwriting and slight problems with movement, such as slowness, rigidity, tremor, and rapid muscular twitching, called myoclonus. Several of these symptoms are similar to those seen in Parkinson's disease, and they differ from the chorea seen in individuals who develop the disease as adults. These young individuals are said to have "akinetic-rigid" HD or the Westphal variant of HD. People with juvenile HD may also have seizures and mental disabilities. The earlier the onset, the faster the disease seems to progress. The disease progresses most rapidly in individuals with juvenile or early-onset HD, and death often follows within 10 years.

Individuals with juvenile HD usually inherit the disease from their fathers. These individuals also tend to have the largest number of CAG repeats. The reason for this may be found in the process of sperm production. Unlike eggs, sperm are produced in the millions. Because DNA is copied millions of times during this process, there is an increased possibility for genetic mistakes to occur. To verify the link between the number of CAG repeats in the HD gene and the age at onset of symptoms, scientists studied a boy who developed HD symptoms at the age of two, one of the youngest and most severe cases ever recorded. They found that he had the largest number of CAG repeats of anyone studied so far-nearly 100. The boy's case was central to the identification of the HD gene and at the same time helped confirm that juveniles with HD have the longest segments of CAG repeats, the only proven correlation between repeat length and age at onset.

A few individuals develop HD after age 55. Diagnosis in these people can be very difficult. The symptoms of HD may be masked by other health problems, or the person may not display the severity of symptoms seen in individuals with HD of earlier onset. These individuals may also show symptoms of depression rather than anger or irritability, or they may retain sharp control over their intellectual functions, such as memory, reasoning, and problem-solving.

There is also a related disorder called senile chorea. Some elderly individuals display the symptoms of HD, especially choreic movements, but do not become demented, have a normal gene, and lack a family history of the disorder. Some scientists believe that a different gene mutation may account for this small number of cases, bu this has not been proven.

**Hyperaldosteronism**

Hyperaldosteronism is the overproduction of the hormone aldosterone from the outer portion (cortex) of the adrenal gland or a tumor containing that type of tissue. Excess aldosterone (pronounced al-do-ster-one) results in low potassium levels (hypokalemia), underacidity of the body (alkalosis), muscle weakness, excess thirst (polydipsia), excess urination (polyuria), and high blood pressure (hypertension). Also called aldosteronism and Conn's syndrome.

**Hyperostosis, Diffuse Idiopathic Skeletal**

Diffuse idiopathic skeletal hyperostosis (DISH) facts

DISH is characterized by unique, flowing calcification along the sides of the contiguous vertebrae of the spine.

Symptoms of DISH include intermittent pains and stiffness in the areas of the bony changes of the spine and inflamed tendons.

DISH is diagnosed when the characteristic flowing calcifications are detected with images of the spine, such as in plain film X-ray methods.

Nonsteroidal anti-inflammatory medications (NSAIDs) can be helpful in both relieving pain and inflammation of DISH.

Diffuse idiopathic skeletal hyperostosis (DISH) is considered a form of degenerative arthritis or osteoarthritis. However, DISH is characterized by unique, flowing calcification along the sides of the contiguous vertebrae of the spine. And, very unlike typical degenerative arthritis, it's also commonly associated with inflammation (tendinitis) and calcification of tendons at their attachments points to bone. This can lead to the formation of bone spurs, such as heel spurs. In fact, heel spurs are common among individuals with DISH. DISH has also been called Forestier's disease

It is not known what causes DISH. DISH is associated with the metabolic syndrome and is more frequent in people with diabetes mellitus.

Symptoms of DISH include intermittent pains in the areas of the bony changes of the spine and inflamed tendons. Stiffness and dull pain, particularly in the upper and lower back, are common. Sometimes pains in these areas can be sharp with certain body movements, such as twisting or bending over.

DISH is only slowly progressive. Calcifications between the vertebrae occur over many years. This calcification can lead to limitation of motion of the involved areas of the spine.

**Hypopituitarism**

This syndrome is characterized by the non-fortuitous association of hypopituitarism and median cleft lip palate. It has been reported in five unrelated cases (three females and two males) and in two case series: one studying midline defects in patients with growth hormone deficiency and the other dealing with growth hormone deficiency in children with cleft lip and palate. Besides cleft lip and palate, several other associated malformations have been reported, mostly involving the midline: absent/hypoplasia of the olfactory bulbs, hypoplastic/absent corpus callosum, absent anterior pituitary, holoprosencephaly, and optic nerve hypoplasia with absence of the septum pellucidum. Non-midline anomalies, such as polysplenia and hydronephrosis, have also been described. Other clinical features are indicative of hypopituitarism : neonatal hypoglycemia, diabetes insipidus, hypoplastic thyroid and adrenal glands, micropenis and cryptorchidism. Intellectual deficit was reported in one female, who also presented with obesity and peculiar facies. The etiology of this association of defects is unknown, but the manifestations suggest that the pituitary gland and oral ectoderm share a common embryological origin. No familial cases have been reported. Growth hormone deficiency should be searched for in case of growth retardation, hypoglycaemia or other hormonal features in a child with cleft lip and palate. Multiviceral failure may lead to early death.

Type 2 is Culler-Jones syndrome, a very rare disease characterized by the association of hypopituitarism and postaxial polydactyly. Other dysmorphic signs (microcephaly, face, hand and foot anomalies) are inconstant. Neonatal hypoglycemia, cryptorchidism, micropenis and short stature are the main clinical signs of hypopituitarism. One patient was found to have an hypothalamic hamartomatous tumor and dysmorphic signs suggestive of Pallister-Hall syndrome. All other patients had minor dysmorphic features and a family history of isolated postaxial polydactyly with an autosomal dominant inheritance. Biological studies confirm growth hormone (GH) deficiency (constant), frequently associated with thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) deficiencies. Brain computerized tomography (CT) scan inconstantly shows hypoplastic anterior pituitary.

**Inappropriate ADH Syndrome**

Inappropriate ADH secretion is a condition that results in the inability to produce dilute urine and imbalance of fluids and electrolytes in the body, particularly lowering blood sodium. Symptoms include nausea, vomiting,muscle cramps, confusion, and convulsions. This syndrome may occur with oat-cell lung cancer, pancreatic cancer, prostate cancer, and Hodgkin's disease, among other disorders. Also known as syndrome of inappropriate ADH secretion or SIADH.

**Intestinal Polyps**

Intestinal polyps are small, mushroom-like abnormalities of the intestine that may have a stalk or be flat with a stalk. They can vary from under 2 millimeters (less than 1/10 of an inch) to over 2 inches in diameter.

Certain sporadic (not inherited) intestinal polyps are a risk factor for colorectal cancer. These polyps - chiefly those classified as adenomas (growths with gland-like characteristics) - are benign, but they may become cancerous, particularly if they grow larger than an inch in diameter.

In most cases, colorectal polyps do not cause symptoms; however, they can cause intermittent bleeding or the passage of mucus with bowel movements. If they are large, they can obstruct the passage of waste material.

Adenomas account for about 70 percent of all colorectal polyps removed as part of colonoscopic examination. Adenomas are present in 30 percent of all adults over the age 50. They arise most often in the rectum and sigmoid colon.

Adenomas are described as pedunculated when they grow on a stalk that connects the head of the polyp to the bowel wall. Flatter polyps that grow directly on the wall of the bowel are called sessile.

About 85 percent are tubular (growing in microscopic tube-like patterns); 5 percent are villous (forming finger-like projections, or fronds); and 10 percent are tubulovillous (intermediate structures that contain both growth patterns). These polyps differ in their structure, texture, and microscopic characteristics; they also differ in their potential for cancerous change.

Invasive cancer develops in roughly 5 percent of all tubular (also called adenomatous) polyps. Villous polyps are less common, but about 40 percent of them become cancerous. Cancer develops in about 22 percent of all tubulo-villous polyps. The most common colorectal types, called hyperplastic polyps or hyperplastic mucosal tags, are harmless.

Scientists believe that many cancers of the large bowel arise from polyps. Thus removing these growths (polypectomy), often through a sigmoidoscope or colonoscope, is one way to prevent colorectal cancer. Because new polyps develop in nearly half of all patients who have had such growths removed, careful follow-up is necessary.

Causes and Risk Factors of Intestinal Polyps

**Family History**: Siblings and parents of patients with colon polyps are at increased risk for colon cancer, particularly when the polyp is diagnosed before the age of 60 or - in the case of siblings - when a parent has had colon cancer.

**Diet**: About 90 percent of all colon cancers arise from polyps in the colon. If doctors could prevent polyps from occurring in the first place, they could reduce the incidence of cancer. In general, most physicians encourage people to eat a low-fat, high-fiber diet, to eat more fruits, vegetables, chicken and fish, and to eat less red meat.

**Smoking**: Smoking may also be a risk factor for colon cancer.

**Obesity**: In some studies, higher body mass was positively associated with an increased risk of adenomas leading to colon cancer.

Symptoms of Intestinal Polyps

Many polyps are asymptomatic; the larger the lesion, the more likely it is to cause symptoms. Rectal bleeding is by far the most frequent complaint. Blood is bright red or dark red, depending on the location of the polyp, and bleeding is usually intermittent.

Some polyps, notably large villous adenomas, may secrete copious amounts of mucus that are released through the rectum.

**Isaacs Syndrome**

Isaacs syndrome is a rare disorder where muscles suffer from stiffness and cramping, particularly limb muscles. More detailed information about the symptoms, causes, and treatments of Isaacs syndrome is available below.

The list of signs and symptoms mentioned in various sources for Isaacs syndrome includes the 8 symptoms listed below:

Persistent myokymia

Lower limb contractures

Increased muscle tone

Cyanotic episodes

Transient stiffness

Reduced motor activity with flexion

Muscle cramps

Difficulty relaxing muscles

**Kartagener Syndrome**

Kartagener syndrome is a genetic syndrome that is characterized by sinusitis, bronchiectasis (widening and inflammation of the bronchi), dextrocardia (heart on the right side of the chest), and infertility. Kartagener syndrome is inherited in an autosomal recessive manner. Kartagener syndrome is usually due to mutation in the gene called DNAI1 on chromosome 9. However, linkage studies have mapped the disease gene to 5p and 19q in some families, indicating that Kartagener syndrome is more than one genetic entity. Also known as ciliary dyskinesia syndrome.

**Kearns-Sayer Syndrome**

Kearns-Sayre syndrome is a neuromuscular disorder characterized by three primary findings:

Progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia, or CPEO);

Abnormal accumulation of colored (pigmented) material on the retina (atypical retinitis pigmentosa), leading to chronic inflammation and progressive degeneration of the retina; and

Heart disease (cardiomyopathy) such as cardiac conduction defects and heart block.

Other findings in the syndrome may include muscle weakness, short stature, hearing loss, and the loss of ability to coordinate voluntary movements (ataxia) due to problems in the part of the brain called the cerebellum.

Kearns-Sayre syndrome is one of the mitochondrial encephalomyopathies. These disorders are due to defects in the DNA of the mitochondria, the cell structures that produce energy. These defects cause the brain and muscles to function abnormally (encephalomyopathy). In about 80% of cases of Kearns-Sayre syndrome, tests reveal deletions in mitochondrial DNA (mtDNA).

There are many other names for the Kearns-Sayre syndrome including: CPEO with myopathy; CPEO with ragged-red fibers; KSS; Mitochondrial cytopathy, Kearns-Sayre type; Oculocraniosomatic syndrome; Ophthalmoplegia-plus syndrome; Ophthalmoplegia with myopathy; and Ophthalmoplegia with ragged-red fibers.

**Keratosis Follicularis**

Keratosis follicularis is a genetic skin disease that is characterized by slowly progressive hardening of the skin (keratosis) around the hair follicles. This disorder is inherited in an autosomal dominant manner and is due to mutation in a gene called ATP2A2 on chromosome 12. Also known as Darier disease.

**Kleine–Levin**Syndrome

Kleine-Levin syndrome, also known as Sleeping beauty syndrome or KLS, is a rare disorder that primarily affects adolescent males (approximately 70 percent of those with Kleine-Levin syndrome are male).

It is characterized by recurring but reversible periods of excessive sleep (up to 20 hours per day). Symptoms occur as "episodes," typically lasting a few days to a few weeks.

Episode onset is often abrupt, and may be associated with flu-like symptoms. Excessive food intake, irritability, childishness, disorientation, hallucinations, and an abnormally uninhibited sex drive may be observed during episodes. Mood can be depressed as a consequence, but not a cause, of the disorder. Affected individuals are completely normal between episodes, although they may not be able to remember afterwards everything that happened during the episode. It may be weeks or more before symptoms reappear. Symptoms may be related to malfunction of the hypothalamus and thalamus, parts of the brain that govern appetite and sleep.

There is no definitive treatment for Kleine-Levin syndrome and watchful waiting at home, rather than pharmacotherapy, is most often advised. Stimulant pills, including amphetamines, methylphenidate, and modafinil, are used to treat sleepiness but may increase irritability and will not improve cognitive abnormalities. Because of similarities between Kleine-Levin syndrome and certain mood disorders, lithium and carbamazepine may be prescribed and, in some cases, have been shown to prevent further episodes. This disorder should be differentiated from cyclic re-occurrence of sleepiness during the premenstrual period in teen-aged girls, which may be controlled with birth control pills. It also should be differentiated from encephalopathy, recurrent depression, or psychosis.

Episodes eventually decrease in frequency and intensity over the course of eight to 12 years.

According to the National Institutes of Health, Kleine-Levin syndrome is characterized by abrupt "episodes" of sleep, which can last for days and sometimes weeks. Symptoms can also include excessive food intake, disorientation and hallucinations. People with Kleine-Levin typically do not remember what happened during their episodes.

**Klippel-Feil Syndrome**

Klippel-Feil syndrome is a congenital disorder involving the fusion of any two of the 7 neck (cervical) vertebrae. Affected individuals have a short neck, low hairline at the nape of the neck, and limited movement of the head. Klippel-Feil syndrome is due to a defect in the early development of the spinal column in the neck and may be assocaited with other birth defects. Also known as Klippel-Feil sequence.

**Klippel-Trenaunay-Weber Syndrome**

Klippel-Trènaunay-Weber (KTW) syndrome is a condition characterized by a triad of findings:

Port-wine stain or "birthmark" (capillary malformations in the skin)

Soft tissue and bony hypertrophy (excessive growth of the soft tissue and/or bones) most often involving a single limb.

Vascular anomalies such as varicose veins.

A port-wine stain is a certain type of hemangioma. This capillary hemangioma has a recognizable appearance. It is usually a deep violet ("port-wine") colored lesion with fairly linear borders. These are most often found on the affected hypertrophied limb. They are generally flat or only slightly raised compared to the surrounding unaffected skin surface. The actual depth of the lesion is unpredictable and less commonly may even affect muscle and bone.

In addition to the port-wine stain, individuals with Klippel-Trènaunay-Weber also develop varicose veins. These often can be seen at birth as a large superficial vein extending from the lower leg all the way up to the buttocks. This vein has been referred to as the "Klippel-Trènaunay" vein and may not be obvious until later in childhood.

Occasionally affected individuals develop an arteriovenous fistula (abnormal connection between an artery and a vein). This is known as the Parkes-Weber variant of KTW. These patients usually have numerous fistulae that can result in heart failure if untreated.

Asymmetric limb hypertrophy is enlargement of one limb compared to the opposite side. For example, an individual with Klippel-Trènaunay-Weber syndrome may have a left leg or arm that is larger than his/her right leg or arm. This asymmetry is found in other inherited syndromes as well. Most commonly in individuals with Klippel-Trènaunay-Weber, the leg is involved more frequently than an arm; however, on occasion there is enlargement of two limbs, a buttock, or part of the trunk of the body.

Although the triad of "port-wine stain, varicosities, and asymmetric limb hypertrophy," is the consistent clinical centerpiece of Klippel-Trènaunay-Weber, there are often other less frequent abnormalities found in those affected by the syndrome. These may include other limb or digit abnormalities such as:

atrophy (a limb that is underdeveloped),

fingers and toes that are disproportionately large or small,

digits that are webbed (syndactyly),

too many digits (polydactyly), or

too few digits (oligodactyly).

In addition to limb abnormalities, there are some other common features, including:

asymmetrical facial hypertrophy (one side of the face may be smaller than the other),

macrocephaly (a large head), or

microcephaly (a small head).

Eye problems may include glaucoma and cataracts. Finally, any of the vascular anomalies can affect the internal organs including the intestinal and urinary tract systems. These may be at risk for spontaneous bleeding, and it is important to evaluate any individual with evidence of superficial abdominal lesions.

Intelligence is usually not impaired in Klippel-Trènaunay-Weber. However, when there are hemangiomas on the face (facial hemangiomatosis), there may also be hemangiomas in the brain which can cause seizures (convulsions) or mental retardation Fortunately, such problems are rare in Klippel-Trènaunay-Weber.

What is the basic defect in Klippel-Trènaunay-Weber syndrome?

It is not completely known, but some researches believe part of the defect is related to the control of angiogenic cells (precursors of blood vessels). Others believe it is caused by some injury to the developing embryo within the womb, resulting in venous compression and resultant abnormal venous pressures, causing varicosities and limb enlargement. In other words, we don't currently know the precise events that lead to the development of Klippel-Trènaunay-Weber.

Most cases of Klippel-Trènaunay-Weber are sporadic. They occur without warning, with no prior case in the family; however recently there have been some cases that run in families.

Most persons with Klippel-Trènaunay-Weber have an enlarged leg and they do relatively well without any significant treatment. It can be helpful to wear compression stockings to prevent venous pooling in the affected extremity (varicose vein management). However, some Klippel-Trènaunay-Weber patients do have considerable pain. Skin ulcers, infections and other skin problems can occur, but usually the treatment is conservative. Surgery is almost never needed.

In 1900 the French physicians Maurice Klippel and Paul Trènaunay reported the case of a patient with a port-wine stain, asymmetrical overgrowth (hypertrophy) of soft tissue and bone together with hemangiomas of the skin In 1907, the eminent London physician F. Parkes Weber reported three more cases, and noted the varicosities. As is often the case in medicine, those who describe a syndrome are often given credit by having the syndrome named after them. Thus, in 1918 it became know as Klippel-Trènaunay-Weber syndrome.

**Kluver-Bucy Syndrome**

Kluver-Bucy Syndrome is a condition where damage to the temporal brain lobes from any of a variety of causes (accident, hypoglycemia, Alzheimer's and others) results in symptoms such as memory loss and abnormal behavior.

The list of signs and symptoms mentioned in various sources for Kluver-Bucy Syndrome includes the 8 symptoms listed below:

Inability to recognize people

Lack of fear reaction

Lack of rage reaction

Hypersexuality

Homosexuality

Bulimia

Hypermetamorphosis

Memory deficiency

**Korsakoff Syndrome**

Korsakoff syndrome is a chronic memory disorder caused by severe deficiency of thiamine (vitamin B-1). Korsakoff syndrome is most commonly caused by alcohol misuse, but certain other conditions also can cause the syndrome.

Thiamine (vitamin B-1) helps brain cells produce energy from sugar. When levels fall too low, brain cells cannot generate enough energy to function properly. As a result, Korsakoff syndrome may develop.

Korsakoff syndrome is most commonly caused by alcohol misuse, but can also be associated with AIDS, chronic infections, poor nutrition and certain other conditions. See causes and risks below.

Korsakoff syndrome is often, but not always, preceded by an episode of Wernicke encephalopathy, which is an acute brain reaction to severe lack of thiamine. Wernicke encephalopathy is a medical emergency that causes life-threatening brain disruption, confusion, staggering and stumbling, lack of coordination, and abnormal involuntary eye movements.

Because the chronic memory loss of Korsakoff syndrome often follows an episode of Wernicke encephalopathy, the chronic disorder is sometimes known as Wernicke-Korsakoff syndrome. But Korsakoff syndrome can also develop in individuals who have not had a prior episode of Wernicke encephalopathy.

Korsakoff syndrome causes problems learning new information, inability to remember recent events and long-term memory gaps. Memory problems may be strikingly severe while other thinking and social skills are relatively unaffected. For example, individuals may seem able to carry on a coherent conversation, but moments later be unable to recall that the conversation took place or to whom they spoke.

Those with Korsakoff syndrome may "confabulate," or make up, information they can't remember. They are not "lying" but may actually believe their invented explanations. Scientists don't yet understand why Korsakoff syndrome may cause confabulation.

Korsakoff syndrome is a clinical diagnosis representing a physician's best judgment about the cause of a person's symptoms. There are no specific lab tests or brain scan procedures to confirm that a person has this disorder. The syndrome may sometimes be hard to identify because it may be masked by symptoms of other conditions common among those who misuse alcohol, including intoxication or withdrawal, infection or head injury.

Scientists don't yet know exactly how Korsakoff syndrome damages the brain. Research has shown that severe thiamine deficiency disrupts several biochemicals that play key roles in carrying signals among brain cells and in storing and retrieving memories. These disruptions destroy brain cells and cause widespread microscopic bleeding and scar tissue.

Most cases of Korsakoff syndrome result from alcohol misuse. Scientists don't yet know why heavy drinking causes severe thiamine deficiency in some alcoholics, while others may be affected primarily by alcohol's effects on the liver, stomach, heart, intestines or other body systems.

Researchers have identified several genetic variations that may increase susceptibility to Korsakoff syndrome. Poor nutrition also may raise risk. Sign up for our enews to receive updates about Alzheimer's and dementia care and research.

Korsakoff syndrome also can be caused by anorexia, overly-stringent dieting, fasting, starvation or weight-loss surgery; uncontrolled vomiting; AIDS; kidney dialysis; chronic infection; or cancer that has spread throughout the body.

**Lafora Disease**

Lafora disease (LD) is a comparatively frequent and particularly severe type of progressive myoclonus epilepsy. The prevalence varies: LD is seen worldwide but is more common in geographic isolates and areas with a high degree of inbreeding. In Western countries, prevalence is estimated to be below 1/1,000,000. Onset occurs during adolescence, with generalised tonic-clonic or clonic-tonic-clonic seizures, action and resting myoclonus, negative myoclonus, and focal occipital seizures with transient amaurosis. The course is marked by prominent and rapid cognitive deterioration (the primary symptoms of which may precede the motor anomalies), and by the progressive increase in intensity of the seizures and myoclonus. Transmission is autosomal recessive. LD is genetically heterogeneous. Mutations/deletions of the _EPM2A_ gene, localised in 1995 to 6q24 (product: laforin), are found in 80% of cases. The less common _EPM2B_ variant is localised on 6p22 (product: malin). However, these two localisations do not account for all cases of LD. The diagnosis of LD may be suspected on the basis of the family history, age at onset, typical appearance of symptoms, rapid worsening of cognitive function and detection of fairly typical electroencephalogram (EEG) features. It can easily be confirmed by axillary skin biopsy with detection of Lafora bodies (polyglucosan aggregates) in the sweat duct cells. Other biopsies, such as brain biopsy, are generally not necessary. Molecular biology is useful for diagnosis but the genetic heterogeneity does not allow LD to be excluded when none of the known mutations are detected. Genetic counselling and prenatal diagnosis are theoretically possible when the genetic anomaly has been documented in an affected member of the family. The treatment of LD with antiepileptic and antimyoclonic drugs remains purely symptomatic. Drugs that may aggravate myoclonus must be avoided. Psychological and social management is of utmost importance in LD. Death occurs 4 to 10 years after onset in typical forms.

**Lambert-Eaton Myasthenic Syndrome**

Lambert-Eaton myasthenic syndrome is an autoimmune disease characterized by weakness and fatigue of the proximal muscles (those near the trunk), particularly the muscles of the pelvic girdle (the pelvis and hips) and the thighs, with relative sparing of eye and respiratory muscles. Lambert-Eaton myasthenic syndrome (LEMS) is associated in 40% of cases with cancer, most often with small cell cancer of the lung and less often with other tumors. The neuromuscular defect in LEMS is due to insufficient release of the neurotransmitter acetylcholine by nerve cells.

LEMS has been treated with pyridostigmine bromide (Mestinon) to increase the transmission of acetylcholine across the neuromuscular junction, a drug called diaminopyridine (DAP) and immunosuppressants (the steroid prednisone, azathioprine, cyclosporine). Plasma exchange provides improvement in some patients with LEMS, as may intravenous immunoglobulin (IVIg). Patients over 50 with a history of long-term smoking are most likely to have an associated tumor. If the tumor is cured, the LEMS may vanish.

LEMS is a "myasthenic syndrome" because the muscle weakness in LEMS is reminiscent of that in myasthenia gravis. Unlike myasthenia gravis, as muscle contractions continue, strength increases in LEMS. The disease is named for Lambert and Eaton who (together with Rooke) described it in 1966. The disease had actually been reported by Anderson and coworkers in 1953 in a man with oat cell cancer of the lung.

**Landau-Kleffner Syndrome**

Landau-Kleffner syndrome (LKS) is a childhood disorder. A major feature of LKS is the gradual or sudden loss of the ability to understand and use spoken language. All children with LKS have abnormal electrical brain waves that can be documented by an electroencephalogram (EEG), a recording of the electric activity of the brain. Approximately 80 percent of the children with LKS have one or more epileptic seizures that usually occur at night. Behavioral disorders such as hyperactivity, aggressiveness and depression can also accompany this disorder. LKS may also be called infantile acquired aphasia, acquired epileptic aphasia or aphasia with convulsive disorder. This syndrome was first described in 1957 by Dr. William M. Landau and Dr. Frank R. Kleffner, who identified six children with the disorder.

LKS occurs most frequently in normally developing children who are between 3 and 7 years of age. For no apparent reason, these children begin having trouble understanding what is said to them. Doctors often refer to this problem as auditory agnosiaor "word deafness." The auditory agnosia may occur slowly or very quickly. Parents often think that the child is developing a hearing problem or has become suddenly deaf. Hearing tests, however, show normal hearing. Children may also appear to be autistic or developmentally delayed.

The inability to understand language eventually affects the child's spoken language which may progress to a complete loss of the ability to speak (mutism). Children who have learned to read and write before the onset of auditory agnosia can often continue communicating through written language. Some children develop a type of gestural communication or sign-like language. The communication problems may lead to behavioral or psychological problems. Intelligence usually appears to be unaffected.

The loss of language may be preceded by an epileptic seizure that usually occurs at night. At some time, 80 percent of children with LKS have one or more seizures. The seizures usually stop by the time the child becomes a teenager. All LKS children have abnormal electrical brain activity on both the right and left sides of their brains.

More than 160 cases have been reported from 1957 through 1990.

The cause of LKS is unknown. Some experts think there is more than one cause for this disorder. All of the children with LKS appear to be perfectly normal until their first seizure or the start of language problems. There have been no reports of children who have a family history of LKS. Therefore, LKS is not likely to be an inherited disorder.

There have not been many long-term follow-up studies of children with LKS. This lack of evidence, along with the wide range of differences among affected children, makes it impossible to predict the outcome of this disorder. Complete language recovery has been reported; however, language problems usually continue into adulthood. The continued language problems can range from difficulty following simple commands to no verbal communication. If recovery takes place, it can occur within days or years. So far, no relationship has been found between the extent of the language impairment, the presence or absence of seizures and the amount of language recovery. Generally, the earlier the disorder begins, the poorer the language recovery.

Most children outgrow the seizures, and electrical brain activity on the EEG usually returns to normal by age 15.

**Langer-Giedion Syndrome**

Langer-Giedon syndrome or trichorhinophalangeal syndrome type 2 is characterized by the association of intellectual deficit and numerous other anomalies including redundant skin, multiple cartilaginous exostoses, characteristic facies and cone-shaped phalangeal epiphyses. The severity and number of these malformations varies between patients. The characteristic facial anomalies consist of a bulbous nose, wide prominent philtrum, thin upper lips, cauliflower ears, sparse hair and a small mandible. Growth retardation, microcephaly, hypotonia and hearing problems have also been reported. The exostosis affects mainly the extremities of the long bones and may lead to pain, functional problems or bone deformation. Exostoses and cone-shaped phalangeal epiphyses appear during the first 5 years of life, during which respiratory infections are frequent. The prevalence is unknown. The syndrome is transmitted in an autosomal dominant manner, but many sporadic cases have been reported. The disease is caused by a microdeletion in chromosome 8q23.3-q24.13 leading to the loss of at least two genes: _TRPS1_ and _EXT1_. Langer-Giedon syndrome can be differentiated from trichorhinophalangeal syndrome type 1 by the presence of the exostoses. Early diagnosis of Langer-Giedon syndrome is essential in order to provide genetic counselling to affected families, and to assure orthopaedic follow-up and management of the growth and hearing problems.

**Leigh Disease**

Leigh's disease is a rare inherited neurometabolic disorder that affects the central nervous system. This progressive disorder begins in infants between the ages of three months and two years. Rarely, it occurs in teenagers and adults.

Leigh's disease can be caused by mutations in mitochondrial DNA or by deficiencies of an enzyme called pyruvate dehydrogenase.

Symptoms of Leigh's disease usually progress rapidly. The earliest signs may be poor sucking ability, and the loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. As the disorder progresses, symptoms may also include generalized weakness, lack of muscle tone, and episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function.

In Leigh's disease, genetic mutations in mitochondrial DNA interfere with the energy sources that run cells in an area of the brain that plays a role in motor movements. The primary function of mitochondria is to convert the energy in glucose and fatty acids into a substance called adenosine triphosphate (ATP). The energy in ATP drives virtually all of a cell's metabolic functions. Genetic mutations in mitochondrial DNA, therefore, result in a chronic lack of energy in these cells, which in turn affects the central nervous system and causes progressive degeneration of motor functions.

There is also a form of Leigh's disease (called X-linked Leigh's disease) which is the result of mutations in a gene that produces another group of substances that are important for cell metabolism. This gene is only found on the X chromosome.

The prognosis for individuals with Leigh's disease is poor. Individuals who lack mitochondrial complex IV activity and those with pyruvate dehydrogenase deficiency tend to have the worst prognosis and die within a few years. Those with partial deficiencies have a better prognosis, and may live to be 6 or 7 years of age. Some have survived to their mid-teenage years.

**Lesch-Nyhan Syndrome**

Lesch-Nyhan syndrome (LNS) is the most severe form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency (see this term), a hereditary disorder of purine metabolism, and is associated with uric acid overproduction (UAO), neurological troubles, and behavioral problems. Estimated prevalence at birth is between 1/380,000 and 1/235,000 live births. Males are generally affected and heterozygous females are carriers (usually asymptomatic). Patients are normal at birth. Psychomotor delay becomes evident within 3 to 6 months with a delay in head support and sitting, hypotonia and athetoid movements. Sandy urine in diapers or crystalluria with urinary tract obstruction are common forms of presentation. Patients have severe action dystonia with baseline hypotonia that may lead to an inability to stand up and walk, and involuntary movements (choreoathetosis and ballismus) associated with voluntary movements increased by stress but not evident at rest. Dysarthria, dysphagia, and opisthotonus are frequent. Spasticity, hyperreflexia and extensor plantar reflex appear later. Patients usually show mild to moderate intellectual deficit. Obsessive-compulsive self-mutilation (lip biting or finger chewing) can appear as soon as teeth are present, does not result from lack of sensation and may be associated with or aggravated by psychological stress. Aggressive behavior (i.e. spitting, abusive language) may be directed against family and friends. Megaloblastic anemia is frequent and may be severe. Microcytic anemia may occur. UAO may result in joint inflammation, gouty arthritis and urolithiasis. Renal failure or acidosis occur rarely. LNS is caused by complete HPRT deficiency due to mutations in the _HPRT1_gene (Xq26). UAO is due to deficient recycling and enhanced synthesis of purine bases. Megaloblastic anemia is supposed to be due to increased folic acid consumption but it does not respond to folic supplementation. The cause of neurological and behavioral symptoms is unknown. Several neurotransmitter disorders and a toxic effect of hypoxanthine excess have been advocated. Diagnosis is suspected when psychomotor delay occurs in a patient with elevated UA in blood and urine. Undetectable HPRT enzyme activity in peripheral blood or in intact cells (erythrocyte, fibroblast) and molecular genetic testing confirm the diagnosis. Differential diagnoses include cerebral palsy, other causes of intellectual deficit, dystonia and self-injury including autism, Tourette syndrome, Cornelia de Lange syndrome (see these terms), idiopathic intellectual deficit, and severe psychiatric disorders. Prenatal diagnosis by amniocentesis or chorionic villus sampling is possible if the mutation has been identified in the family. Inheritance is X-linked recessive and genetic counseling is essential. UAO is managed with allopurinol, urine alkalinization, and hydration. Doses must be adjusted to avoid xanthine urolithiasis. There is no treatment for the neurological dysfunction. Spasticity and dystonia can be managed with benzodiazepines (diazepam, alprazolam) and gamma-aminobutyric acid inhibitors (baclofen, tizanidine). Physical rehabilitation (i.e. management of dysarthria and dysphagia), devices to enable hand control, walking aids, and posture management to prevent deformities are recommended. Self-injury requires physical restraints, behavioral and pharmaceutical treatment (gabapentin, carbamazepine). Patients may die from aspiration pneumonia or complications from chronic nephrolithiasis and renal failure. With optimal care, few patients live beyond 40 years and most are confined to a wheelchair.

**Leukodystrophy, Globoid Cell**

Krabbe's disease, also called globoid cell leukodystrophy, is an autosomal recessive condition resulting from galactosylceramidase (or galactocerebrosidase) deficiency, a lysosomal enzyme that catabolizes a major lipid component of myelin. Incidence in France is an estimated 1:150,000 births. The disease leads to demyelination of the central and peripheral nervous system. Onset generally occurs during the first year and the condition is rapidly progressive, but juvenile, adolescent or adult onset forms have also been reported, with a more variable rate of progression. The classic infantile form accounts for 85 to 90% of cases. Initial symptoms include increasing irritability, hypertonia, hyperesthesia, and signs of peripheral neuropathy. Later on, hypertonic episodes with opisthotonos occur frequently, and convulsions may appear. As the disease progresses, blindness and deafness occur, followed by a vegetative state, and finally by hypotonia. In the forms with later onset the first signs are often gait disturbancies (spastic paraparesis or ataxia), hemiplegia, visual loss, with or without peripheral neuropathy. Mental deterioration is variable (usually absent in adult forms). The gene coding for galactosylceramidase is located on 14q31 and has been identified. Two mutations are more frequently observed (65% of alleles in France). Diagnosis is established from enzyme assay (galactosylceramidase deficiency). There are several natural animal models (mouse, dog, monkey). Pathognomonic globoid cells are derived from macrophages and induced by non-hydrolysed galactosylceramides. The early destruction of oligodendrocytes is considered to be due to the accumulation of a cytotoxic metabolite (galactosylsphingosine or 'psychosine').

**Li-Fraumeni Syndrome**

Syndrome, Li-Fraumeni (LFS) is an extraordinary cancer family syndrome. People with LFS have a tendency to develop a great diversity of tumors.

LFS was first discovered in 1969. By reviewing the medical records and death certificates of children with a relatively rare tumor, a soft tissue sarcoma called rhabdomyosarcoma, Drs. Fred Li and Joe Fraumeni at the National Cancer Institute identified several families in which siblings or cousins also had a childhood sarcoma. These same families had exceptional histories of breast cancer and other tumors and proved to have LFS.

The spectrum of cancers in LFS has been shown to include breast cancer, soft tissue sarcomas, brain tumors, a bone tumor called osteosarcoma, leukemia, and a tumor of the adrenal gland (adrenocortical carcinoma): an incredible range of malignancies.

The Li-Fraumeni syndrome has been found to be due to a mutation (a heritable change) in a gene that normally serves to curb cancer: the p53 tumor-suppressor gene. LFS has been of considerable importance to the understanding of the genetics and molecular biology of cancer.

**Long QT Syndrome**

Long QT syndrome is a disorder of the heart's electrical system that predisposes individuals to irregular heartbeats, fainting spells, and sudden death. The irregular heartbeats are typically brought on by stress or vigorous activity. Abbreviated LQTS. LQTS is often symptomless and undiagnosed, but it is well known as a cause of sudden cardiac death in young, apparently healthy people, most notably competitive athletes. QT refers to an interval seen in an electrocardiogram (EKG) test of heart function. There are multiple genetic forms of LQTS. Romano-Ward syndrome is an autosomal dominant form of LQTS. The Jervell and Lange-Nielsen syndrome is an autosomal recessive form of LQTS and is characterized by congenital profound bilateral sensorineural hearing loss and long QT interval.

**Lymphoma, Mantle-Cell**

Mantle cell lymphoma is a rare form of malignant non-Hodgkin lymphoma (see this term) affecting B lymphocytes in the lymph nodes in a region called the "mantle zone". It accounts for 2-10% of lymphomas. Prevalence is estimated at about 1/25,000. Mantle cell lymphoma affects middle-aged adults, especially around 65 years (range 35-85 years) with males affected more than females (ratio M/F: 4:1). At diagnosis, most patients present with a disseminated form of the disease. Mantle cell lymphoma is often associated with generalized adenopathy (90% of cases), gastrointestinal disorders (60% of cases) and bone marrow involvement (55-80% of cases). Fever and impaired general condition (fatigue, loss of appetite and weight loss) may occur. Mantle cell lymphoma is caused by a chromosomal translocation t(11;14) (q13;q32), which juxtaposes the_CCND1_ gene to the gene encoding for heavy chain immunoglobulins, leading to abnormally high expression of cyclin D1, a cell cycle regulator, in the nucleus of lymphoma cells. Diagnosis is based on lymph node biopsy revealing the presence of tumor cells. Phenotypic immunohistochemical analysis as well as evidence of abnormal expression of cyclin D1 (or the translocation t(11;14) by FISH or conventional cytogenetics) is necessary to confirm the diagnosis. Analysis of the stage of the disease is done with imaging (ultrasound, CT scanning and MRI) as well as bone marrow analysis (biopsy). Endoscopic examination should be used to detect intestinal involvement. Differential diagnoses include follicular lymphoma (see this term) and other forms of lymphoma. Treatment of mantel cell lymphoma includes intensive chemotherapy combined with monoclonal antibodies. In younger patients, autologous stem cell transplantation is currently suggested. Torisel (chemotherapy) is a product that has received European market authorization as an orphan drug for refractory or relapsing disease. Rare localized forms of the disease may benefit from radiotherapy. Few patients (30%) have a complete response to current treatments. The median overall survival time reported in the literature is 3-5 years.

**Machado-Joseph Disease**

Machado-Joseph disease type 1 is a rare, usually severe subtype of Machado-Joseph disease (SCA3/MJD, see this term) characterized by the presence of marked pyramidal and extrapyramidal signs. The prevalence of this form of MJD is not known. It accounts for 13% of all SCA3 cases. Onset is generally early (mean of 24 years) and symptoms progress rapidly. MJD Type 1 patients generally present with cerebellar signs and external progressive ophthalmoplegia with variable degrees of pyramidal manifestations (spasticity, hyperreflexia). Patients also have extrapyramidal signs including dystonia. The disease is caused by CAG repeat expansion mutations in the _ATXN3_ gene (14q21). Patients with this subtype of SCA3 tend to have larger CAG expansions than those with other subtypes. MJD follows an autosomal dominant pattern of inheritance.

Machado-Joseph disease type 2 is a subtype of Machado-Joseph disease (SCA3/MJD, see this term) with intermediate severity characterized by an intermediate age of onset, cerebellar ataxia and external progressive ophthalmoplegia, with variable pyramidal and extrapyramidal signs. The prevalence of this form of MJD is not known. It is the most frequent form of SCA3 and accounts for 57% of all SCA3 cases. Patients develop the disease in middle adulthood (mean age 40 years). If present, extrapyramidal and peripheral manifestations are mild. Some patients progress within 5 to 10 years to type 1 MJD (see this term) if significant extrapyramidal signs develop, or type 3 MJD (see this term) if significant peripheral signs appear. The disease is caused by CAG repeat expansion mutations in the _ATXN3_ gene (14q21). MJD follows an autosomal dominant pattern of inheritance.

Machado-Joseph disease type 3 is a subtype of Machado-Joseph disease (SCA3/MJD, see this term) of milder severity characterized by late onset, slower progression, and peripheral amyotrophy. The prevalence of this form of MJD is not known. It accounts for 30% of all SCA3 cases. The mean age of onset is 46 years and signs include cerebellar ataxia and external progressive ophthalmoplegia along with peripheral amyotrophy, with or without mild pyramidal and extrapyramidal features. The disease is caused by CAG repeat expansion mutations in the _ATXN3_ gene (14q21). MJD follows an autosomal dominant pattern of inheritance.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common subtype of type 1 autosomal dominant cerebellar ataxia (ADCA type 1; see this term), a neurodegenerative disorder, and is characterized by ataxia, external progressive ophthalmoplegia, and other neurological manifestations. Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations: the highest prevalence has been found in the Azores (Flores Island (1/239)), intermediate prevalence rates in Portugal, Germany, the Netherlands, China and Japan, and lower prevalence in North America, Australia and India. Accurate estimates of prevalence are not available. However, SCA3 is the most common form of ADCA1 in most genetically characterized populations and accounts for up to 72 % of families with ataxia. Based on an English language literature review about 600 cases have been published. SCA3 is divided into 3 forms. SCA3 type 1 (MJD Type 1, see this term) is associated with ataxia, ophthalmoparesis, pyramidal signs such as spasticity and hyperreflexia, and extrapyramidal signs including dystonia and other movement disorders presenting in adolescence. SCA3 type 2 (MJD Type 2, see this term) presents in middle adulthood with ataxia, spasticity, and dystonia. SCA3 type 3 (MJD Type 3, see this term) occurs after the age of 40 and includes ophthalmoparesis and anterior horn cell disease, i.e. fasciculations, atrophy, and weakness. Parkinsonism can also be a feature of SCA3. A likely overlooked but common feature is impairment of temperature sensation involving the entire body. The disease is associated with a CAG repeat expansion mutation in the_ATXN3_ gene (14q21) with anticipation phenomenon. The normal repeat length is 13-41 whereas repeat lengths causing SCA3 are greater than 56. Diagnosis is based on the clinical picture, familial history and ultimately on genetic testing. Differential diagnosis is broad and includes other types of SCA which may have similar features. Prenatal diagnosis and pre-manifestation diagnosis in patients with a family history of SCA can be offered. SCA3 follows an autosomal dominant pattern of inheritance with full penetrance and anticipation phenomenon. Genetic counseling is recommended in symptomatic patients or those with a family history of the disorder due to known SCA mutation, and pre-symptomatic testing should be discussed in adults. In the absence of specific treatments to slow or stop disease progression, care is supportive. For example, parkinsonism, restless legs syndrome, spasticity, sleep disorders and depression can be treated pharmacologically. Dystonia and spasticity can be managed with local botulinum toxin injections. Occupational and physical therapy are essential. Speech therapy may also be of benefit for managing dysarthria. Prognosis is poor but patients have been reported to survive for decades after onset of symptoms.

**Mallory-Weiss Syndrome**

Mallory-Weiss syndrome is a laceration of the lining of the gastroesophageal junction or just above it - often caused by severe vomiting.

The list of signs and symptoms mentioned in various sources for Mallory-Weiss syndrome includes the 8 symptoms listed below:

Esophageal bleeding

Vomiting

Severe retching

Vomiting blood

Melena

Pallor

Tachycardia

Hiccups

**Marek Disease**

Marek's disease is a viral disease that affects poultry - it is very contagious and is aherpes virus. The virus tends to affect the nerves and cause tumors in internal organs. Poultry may be unable to lay eggs or may even die. Young birds are more susceptible than older birds with death most common between the ages of 8 and 20 weeks. The virus may attack the nervous system and result in paralysis or it may attack the visceral system and cause tumors in the internal organs. Some birds may die without any obvious symptoms.

The list of signs and symptoms mentioned in various sources for Marek's disease includes the 15 symptoms listed below:

Progressive limb paralysis

Progressive neck paralysis - less common

Progressive wing paralysis - less common

Loss of ability to stand

Paralysis

Uncoordination

Internal organ tumors

Swollen liver

Swollen spleen

Loss of appetite

Loss of weight

Anemia

Pale combs

Shrunken combs

Dehydration

**Marfan Syndrome**

Marfan syndrome is a heritable condition that affects the connective tissue. The primary purpose of connective tissue is to hold the body together and provide a framework for growth and development. In Marfan syndrome, the connective tissue is defective and does not act as it should. Because connective tissue is found throughout the body, Marfan syndrome can affect many body systems, including the skeleton, eyes, heart and blood vessels, nervous system, skin, and lungs.

Marfan syndrome affects men, women, and children, and has been found among people of all races and ethnic backgrounds. It is estimated that at least 1 in 5,000 people in the United States have the disorder.

Marfan syndrome affects different people in different ways. Some people have only mild symptoms, while others are more severely affected. In most cases, the symptoms progress as the person ages. The body systems most often affected by Marfan syndrome are:

**Skeleton** - People with Marfan syndrome are typically very tall, slender, and loose-jointed. Because Marfan syndrome affects the long bones of the skeleton, a person's arms, legs, fingers, and toes may be disproportionately long in relation to the rest of the body. A person with Marfan syndrome often has a long, narrow face, and the roof of the mouth may be arched, causing the teeth to be crowded. Other skeletal problems include a sternum (breastbone) that is either protruding or indented, curvature of the spine (scoliosis), and flat feet.

**Eyes**- More than half of all people with Marfan syndrome experience dislocation of one or both lenses of the eye. The lens may be slightly higher or lower than normal, and may be shifted off to one side. The dislocation may be minimal, or it may be pronounced and obvious. One serious complication that may occur with this disorder is retinal detachment. Many people with Marfan syndrome are also nearsighted (myopic), and some can develop early glaucoma (high pressure within the eye) or cataracts (the eye's lens loses its clearness).

**Heart and blood vessels (cardiovascular system)** - Most people with Marfan syndrome have problems associated with the heart and blood vessels. Because of faulty connective tissue, the wall of the aorta (the large artery that carries blood from the heart to the rest of the body) may be weakened and stretch, a process called aortic dilatation. Aortic dilatation increases the risk that the aorta will tear (aortic dissection) or rupture, causing serious heart problems or sometimessudden death. Sometimes, defects in heart valves can also cause problems. In some cases, certain valves may leak, creating a "heart murmur," which a doctor can hear with a stethoscope. Small leaks may not result in any symptoms, but larger ones may cause shortness of breath, fatigue, and palpitations (a very fast or irregular heart rate).

**Nervous system** - The brain and spinal cord are surrounded by fluid contained by a membrane called the dura, which is composed of connective tissue. As someone with Marfan syndrome gets older, the dura often weakens and stretches, then begins to weigh on the vertebrae in the lower spine and wear away the bone surrounding the spinal cord. This is called dural ectasia. These changes may cause only mild discomfort; or they may lead to radiated pain in the abdomen; or to pain, numbness, or weakness in the legs.

**Skin** - Many people with Marfan syndrome develop stretch marks on their skin, even without any weight change. These stretch marks can occur at any age and pose no health risk. However, people with Marfan syndrome are also at increased risk for developing an abdominal or inguinal hernia, in which a bulge develops that contains part of the intestines.

**Lungs** - Although connective tissue problems make the tiny air sacs within the lungs less elastic, people with Marfan syndrome generally do not experience noticeable problems with their lungs. If, however, these tiny air sacs become stretched or swollen, the risk of lung collapse may increase. Rarely, people with Marfan syndrome may have sleep-related breathing disorders such as snoring, or sleep apnea (which is characterized by brief periods when breathing stops).

**Meckel Diverticulum**

Diverticulum, Meckel's is an outpouching of the small bowel. About 1 in every 50 (2%) people has a Meckel's diverticulum. It is usually 2 inches long and is located about 2 feet before the junction of the small bowel with the colon (the large intestine) in the right lower abdomen.

Meckel's diverticulum can become inflamed, ulcerate and perforate (break open or rupture). This can cause obstruction of the small bowel. Ulceration of a Meckel can cause lower intestinal bleeding.

If it is inflamed or perforated, Meckel's diverticulum is usually removed by surgery.

**Meige Syndrome**

Meige syndrome is a neurological movement disorder involving symptoms such as involuntary facial movements and eye muscle spasms.

The list of signs and symptoms mentioned in various sources for Meige syndrome includes the 16 symptoms listed below:

Forceful opening of mouth

Lip retraction

Spasm of platisma

Tongue protrusion

Clamped jaw

Pursed lips

Dysphonia

Intermittent involuntary closure of eyelid

Torticollis

Trunk dystonia

Limb dystonia

Eye muscle spasm

Tongue spasm

Throat spasm

Respiratory tract spasm

Breathing difficulties

The exact cause of Meige syndrome is not known, although research suggests that both genetic and environmental factors are involved. The specific genes involved in affecting Meige syndrome have not been identified.

**Melkersson-Rosenthal Syndrome**

The Melkersson-Rosenthal syndrome is a rare disorder characterized by a triad of recurrent orofacial swelling, relapsing facial paralysis and fissured tongue and onset in childhood or early adolescence. It has an estimated incidence of 8/10,000. The etiology is unknown but hereditary predisposition is suspected. Melkersson-Rosenthal syndrome is a neurological disorder characterized by facial swelling, especially of the lips. Partial paralysis may occur, and the tongue may develop folds or furrows. Symptoms often begin in early adolescence. The cause of Melkersson-Rosenthal syndrome is unknown.

The list of signs and symptoms mentioned in various sources for Melkersson-Rosenthal Syndrome includes the 13 symptoms listed below:

Facial swelling

Lip swelling

Partial facial paralysis

Tongue abnormalities

Tongue folds

Tongue furrows

Episodes of facial paralysis

Episodes of facial edema

Episodes of swollen lip

Episodes of swollen cheeks

Episodes of swollen chin

Episodes of swollen tongue

Scrota tongue

The follow list shows some of the possible medical causes of Melkersson-Rosenthal Syndrome that are listed by the Diseases Database:

Sarcoidosis

Crohn's disease

Melkersson-Rosenthal-Schuermann syndrome

**Meniere's Disease**

Although the cause of Meniere's disease is unknown, it probably results from an abnormality in the way fluid of the inner ear is regulated. In most cases only one ear is involved, but both ears may be affected in about 10% to 20% of patients. Meniere's disease typically starts between the ages of 20 and 50 years of age (although it has been reported in nearly all age groups). Men and women are equally affected. The symptoms may be only a minor nuisance, or can become disabling, especially if the attacks of vertigo are severe, frequent, and occur without warning. Meniere's disease is also called idiopathic endolymphatic hydrops.

The symptoms of Meniere's disease typically include at least several of the following:

**Episodic rotational vertigo: **Attacks of a spinning sensation accompanied by disequilibrium (an off-balanced sensation), nausea, and sometimes vomiting. This is usually the most troublesome symptom. The vertigo usually last 20 minutes to two hours or even longer. During attacks, patients are very disabled, and sleepiness may follow. An off-balanced sensation may last for several days.

**Tinnitus:**A roaring, buzzing, machine-like, or ringing sound in the ear. It may be episodic with an attack of vertigo or it may be constant. Usually the tinnitus gets worse or will appear just before the onset of the vertigo.

**Hearing loss:**It may be intermittent early in the onset of the disease, but overtime it may become a fixed hearing loss. It may involve all frequencies, but most commonly occurs in the lower frequencies. Loud sounds may be uncomfortable and appear distorted in the affected ear.

**Ear fullness:** Usually this full feeling occurs just before the onset of an attack of vertigo.

**Methemoglobinemia**

Methemoglobinemia is the presence in the blood of methemoglobin, a form of hemoglobin that is useless for carrying oxygen and delivering it to tissues throughout the human body. A small amount of methemoglobin is normally present in blood but the conversion of a larger fraction of hemoglobin into methemoglobin, which does not function well as an oxygen carrier, results in clinical symptoms. Since hemoglobin is the key carrier of oxygen in the blood, its replacement by methemoglobin can cause a slate gray-blueness of the skin (cyanosis), and potentially cause more serious symptoms due to insufficient oxygen.

In more technical terms, methemoglobin is a transformation product of normal oxyhemoglobin. It is created by the oxidation of the ferrous iron present in the heme part of hemoglobin to ferric iron.

Methemoglobinemia may be acquired anytime in life by exposure to a number of different chemical agents such as nitrites or certain medications (acquired methemoglobulinemia) or it may be present at birth (congenital) due a genetic condition.

**Mikulicz' Disease**

Mikulicz's Disease is a rare condition involving enlargement of the salivary and tear-producing glands. If the enlargement as a result of another condition, it is called Mikulicz syndrome.

The list of signs and symptoms mentioned in various sources for Mikulicz's Disease includes the 10 symptoms listed below:

Enlarged salivary glands

Enlarged tear-producing glands

Narrowed eye slits

Dry mouth

Absent tears

Reduced tears

Blurred vision

Hard lumps in tear gland

Hard lumps in salivary glands

Painless gland lumps

To research the causes of Mikulicz's Disease, consider researching the causes of these these diseases that may be similar, or associated with Mikulicz's Disease:

Benign parotid gland lesion

Tuberculosis

Sarcoidosis

Lymphoma

Sjogren's syndrome

Sialadenosis

**Miller Fisher Syndrome**

Miller Fisher syndrome is a rare, acute polyneuropathy characterized by ataxia (abnormal muscle coordination), ophthalmoplegia (paralysis of the eye muscles), and areflexia (absence of the reflexes). The disorder is a variant of Guillain-Barre syndrome.

The list of signs and symptoms mentioned in various sources for Miller Fisher Syndrome includes the 5 symptoms listed below:

Ataxia

Ophthalmoplegia

Areflexia (absence of reflexes)

Generalized muscle weakness

Respiratory failure

To research the causes of Miller Fisher Syndrome, consider researching the causes of these these diseases that may be similar, or associated with Miller Fisher Syndrome:

Gullian Barre syndrome

Descending paralysis

Diplopia

Numbness

Dizziness

Ophthalmoplegia

Plasmapheresis

The prognosis for most individuals with Miller Fisher syndrome is good. In most cases, recovery begins within 2 to 4 weeks of the onset of symptoms, and may be almost complete within 6 months. Some individuals are left with residual deficits. Very rarely (in less than 3 percent of cases) relapses may occur.

**Mobius Syndrome**

Moebius syndrome is a congenital form of oculofacial paralysis. Approximately 300 cases have been reported in the literature to date. The first manifestation of the disease is an impaired ability to suck. Affected newborns also display excessive drooling and present with strabismus. Later, lack of facial expression, inability to smile, and absence of blinking and of lateral eye movements dominate the clinical picture. Other anomalies may be associated, such as tongue deformation (and hence speech difficulties) and jaw abnormalities. Limb deformities are observed in one third of patients and can include club-foot, missing or webbed fingers or Poland's anomaly. Most children suffer from low muscle tone, especially in the upper part of the body, leading to a delayed acquisition of walking. Mild intellectual deficit occurs in approximately 10 percent of cases. Moebius syndrome is caused by abnormal development of the 7th cranial nerve (facial) in all patients and of 6th cranial nerve (abducens) in 75% of the cases. Other cranial nerves can also occasionally be affected (the 3rd, 4th, 5th, 9th, 10th and 12th). Most cases of Moebius syndrome are isolated cases with no notable family history. The disease does not evolve and management is essentially symptomatic. Infants may require special bottles or feeding tubes to maintain sufficient nutrition. Patients can also benefit from physical and speech therapy to improve their gross motor skills and coordination, and to gain better control over speaking and eating. Strabismus is usually correctable with surgery and limb and jaw deformities may also often be improved through surgical intervention. Muscle graft can give the face some mobility and allow patients to smile.

**Möbius syndrome - axonal neuropathy - hypogonadotropic hypogonadism**

This syndrome is characterized by the association of Möbius syndrome (congenital facial palsy with impaired ocular abduction; see this term) with peripheral axonal neuropathy and hypogonadotropic hypogonadism. Only seven cases have been described in the literature so far. All of the reported cases were sporadic.

**Moyamoya Disease**

Moyamoya disease is an angiogenic disease caused by progressive stenosis of the cerebral arteries located at the base of the brain. This disease remains asymptomatic in many cases: radiological criteria are observed in the absence of clinical signs in 1/2,000 adults in Japan, whereas the prevalence of Moyamoya syndrome is 1/32,000 in the general Japanese population. It is ten times less frequent in Europe. It affects the intracerebral part of the internal carotids and causes a secondary collateral network to develop following a pattern resembling cigarette smoke ('moya-moya' in Japanese). Spontaneous progression may be insidious with headaches, epileptic seizures, language disorders and upper cerebral dysfunction. More often, acute and focal signs such as hemiplegia and sometimes hemichorea occur. Repeated deficiencies and frequently alternating hemiplegia represent the usual picture. Episodes are precipitated by hyperpnoea. The clinical picture can vary according to age, adults more often suffer from hemorrhages and children from ischemic accidents. Moyamoya disease may be secondary to a known cause (drepanocytic anemia, radiotherapy, or in some patients affected by neurofibromatosis type I or William's syndrome; see these terms), or idiopathic. Hereditary forms of the disease, following an autosomal recessive pattern of transmission, have been described in about 10% of the cases. Various genetic localizations (chromosomes 3, 6, 8 and 17) have been reported in these familial forms. The diagnosis is suggested by brain scans and magnetic resonance images showing multiple ischemic accidents of different ages, possibly hemorrhage and abnormal vessels at the base of the brain. Conventional angiography is used to ascertain the diagnosis and to assess the stage of evolution of the disease. A variety of surgical techniques that stimulate peripheral angiogenesis can be proposed to compensate for deep ischemia. Treatment should begin early in the disease course to prevent vascular stenoses from affecting brain parenchyma. Mortality rates are increased, especially by the occurrence of hemorrhagic accidents.

**Mucocutaneous Lymph Node Syndrome**

Mucocutaneous lymph node syndrome is a syndrome of unknown origin that mainly affects young children. It causes fever, reddening of the eyes (conjunctivitis) and lips and mucous membranes of the mouth, ulcerative gum disease (gingivitis), swollen glands in the neck (cervical lymphadenopathy), and a rash that is raised and bright red (maculoerythematous) in a glove-and-sock fashion over the hands and feet. The skin there becomes hard, swollen (edematous), and peels. The name "mucocutaneous lymph node syndrome" is descriptive because the disease is characterized by the typical changes in the mucus membranes that line the lips and mouth and by the enlarged and tender lymph glands. Also called Kawasaki's syndrome, the mucocutaneous lymph node syndrome was first described in the late 1960's in Japan by the pediatrician Tomisaku Kawaski.

**Mullerian Ducts**

Mullerian Ducts are two ducts of the embryo which empty into the cloaca, and which in the female develop into vagina, uterus and oviducts; in the male they disappear except for the vestigial vagina masculina and the appendix testis.

**Multiple Endocrine Neoplasia Type 1**

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary cancer syndrome marked mainly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. It occurs in approximately one in 30,000 individuals. Two different forms, sporadic and familial, have been described. The sporadic form presents with two of the three principal MEN1-related endocrine tumours (parathyroid adenomas, entero-pancreatic tumours and pituitary tumours) within a single patient, while the familial form consists of a MEN1 case with at least one first-degree relative showing one of the characteristic endocrine tumours. Other endocrine and non-endocrine lesions, such as adrenal cortical tumours, carcinoids of the bronchi, gastrointestinal tract and thymus, lipomas, angiofibromas, and collagenomas have been described. The syndrome is transmitted as an autosomal dominant trait. MEN1 syndrome is caused by inactivating mutations of the _MEN1_ tumour suppressor gene. _MEN1_ maps to chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, which shows no sequence homology to other known human proteins. This gene is probably involved in the regulation of several cell functions such as DNA replication and repair, and transcriptional machinery. The combination of clinical and genetic investigations, together with the improving knowledge of the molecular genetics of the syndrome, has led to progress in the clinical management of patients. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, for whom routine surveillance (regular biochemical and/or radiological screening to detect the development of MEN1-associated tumours and lesions) is recommended.

Multiple endocrine neoplasia type 2 (MEN2) is a polyglandular neoplasm syndrome characterized by the occurrence of medullary thyroid carcinoma (MTC), pheochromocytoma (PCC; see these terms) and, in one variant, primary hyperparathyroidism (PHPT).

The total prevalence of all MEN2 variants is approximately 1/35,000. Of the three MEN2 subtypes, MEN2A accounts for about 70%-80% of cases, familial medullary thyroid carcinoma (FMTC) for 10-20% of cases and MEN2B for 5% of all cases (see these terms).

The clinical manifestations of MEN2 are related to the syndrome subtypes and depend on the specific mutation in the _RET_ gene. MEN2 can affect all age groups, with disease symptoms beginning in infancy to early childhood (MEN2B) or adulthood (MEN2A and FMTC). MTC is seen in all forms of MEN2, and is usually the first manifestation of the disease and arises in the lateral thyroid lobes. In MEN2A, MTC is associated in 50% of cases with PCC and in 20-30% with hyperparathyroidism. MEN2B is characterized by MTC and in 50% of cases with PCC, but unlike MEN2A, PHPT is not present. Patients instead exhibit mucosal neuromas of the lips and tongue, bumpy lips, ganglioneuromatosis of the gastrointestinal tract and marfanoid habitus. Patients with PCC will exhibit additional symptoms of headache, palpitations, nervousness, hypertension and tachycardia. If PHPT is present, symptoms such as depression, muscle weakness and fatigue may be present. MTC can remain in the thyroid gland or can spread to distant sites in the more aggressive forms of the disease, leading to bone pain and diarrhea from increased calcitonin (Ct) concentrations.

MEN2 is caused by a germline activating mutation in the _RET_ proto-oncogene that encodes a receptor tyrosine kinase which transduces growth and differentiation signals in the neural crest. The specific _RET_ mutations are directly related to the MEN2 subtypes and thus to the aggressiveness of MTC and presence of other endocrine tumors.

Diagnosis of MEN2 involves the diagnosis of MTC, PCC and eventually PHPT. For the diagnosis of MTCs a thyroid scan is performed and plasma Ct is measured. Elevated Ct (10pg/ml) is specific to this disease. PCC is diagnosed by measuring plasma and/or 24h urinary excretion of catecholamines and metanephrines along with MRI images.

Differential diagnoses include MTC and Hirschsprung's disease (see these terms).

Antenatal diagnosis is possible and can identify mutations in the _RET_ gene of offspring.

MEN2 is an autosomal-dominant syndrome and parents have a 50% chance of passing on the _RET_ gene to their offspring. Screening of all first-degree relatives should be performed in order to identify _RET_ mutated gene carriers. Specific _RET_codon mutations correlate with the MEN2 variants and are used to guide treatment plans.

Management of MEN2 involves treatment of MTC, PCC and PHPT. Total thyroidectomy with systematic dissection of all lymph nodes is the standard surgery performed. For patients with PCC, endoscopic adrenal-sparing surgery has become the treatment of choice. PCC can be lethal and should be removed before a thyroidectomy or any other surgical intervention. In MEN2A, PHPT can be treated by excising enlarged parathyroid glands while leaving at least one intact. A prophylactic thyroidectomy is recommended for all patients with an identified _RET_ mutation, but the timing of this surgery is much debated. It has been recommended that they be performed in the first year of life for children with MEN2B and between the ages of 2-5 in patients with MEN2A or FMTC. Lifelong thyroid hormone supplementation will be necessary.

The prognosis of MEN2 depends on the stage at which MTC is diagnosed and quality of initial surgical treatment. Early diagnosis and complete initial resection of tumors increase life expectancy.

Multiple endocrine neoplasia 2A (MEN2A) syndrome is a form of MEN2 syndrome (see this term) characterized by medullary thyroid carcinoma (MTC; see this term) in combination with pheochromocytoma (see this term) and primary mild hyperparathyroidism (resulting from hyperplasia or adenoma of the parathyroid cells).

Prevalence of MEN2A is approximately 1/40,000 and it accounts for about 70-80% of all MEN2 syndromes.

Disease onset is usually prior to age 35 years (usually between 5-25 years) with MTC generally being the first manifestation. Rare variants of MEN2A can be associated with cutaneous lichen amyloidosis (skin lesions usually located on the upper back and appearing before MTC) or excessive production of corticotrophin. Patients can also develop disturbances in gut transit that resemble those seen in Hirschsprung's disease (see this term) which lead to megacolon and chronic colonic obstruction.

Missense mutations altering the conserved cysteine codons adjacent to the transmembrane domain of the _RET_ proto-oncogene have been identified in the germline DNA of patients with MEN2A.

Transmission is autosomal dominant.

The prognosis of MEN2A is better than that of MEN2B.

Multiple endocrine neoplasia 2B (MEN2B) syndrome is a form of MEN2 syndrome (see this term) characterized by medullary thyroid carcinoma (MTC, see this term), pheochromocytoma (see this term), mucosal ganglioneuromas and marfanoid habitus.

The exact prevalence is unknown but it accounts for 5-10% of all MEN2 syndromes and is the most aggressive form of the disease.

Onset usually occurs earlier than MEN2A (see this term) and most frequently in infants and young children. Contrary to MEN2A syndrome, hyperparathyroidism is not present. Chronic constipation, abdominal distension, diarrhea or megacolon at birth are often the initial signs of the disease due to ganglioneuromatosis of the gastrointestinal tract. Patients also exhibit developmental anomalies such as mucosal neuromas of the lips and tongue, bumpy lips, and marfanoid habitus (with skeletal abnormalities and joint laxity).

A single mutation at codon 918 in the tyrosine kinase domain of the _RET_ proto-oncogene has been associated with the MEN2B phenotype.

Transmission is autosomal dominant.

Patients with MEN2B have a poorer prognosis and a higher mortality rate than in those with MEN2A.

**Munchausen Syndrome by Proxy**

Munchausen syndrome by proxy (MSBP) features a caretaker covertly abusing a child by faking or causing symptoms in the child victim. MSBP is also called Munchausen by proxy (MBP), factitious disorder by proxy, induced illness, or fabricated illness and is a mental disorder that belongs to the group of mental illnesses called factitious disorders. Like other factitious disorders, it is characterized by a feigning or intentional production of physical or mental-health symptoms for the sole purpose of assuming the sick role. While the reported frequency with which it occurs seems low at one to three in 100,000, it is likely that the actual number of undiscovered MSBP cases is much higher. MSBP tends to affect males as often as females. Affected individuals are usually 4 years old or younger and mothers are the perpetrators 75%-90% of the time. The tendency toward maternal perpetrators may be more a result of women continuing to be the primary caregiver than any gender-based predisposition to the disorder. MSBP can take two years or more from the beginning or onset of symptoms to when it is diagnosed. Victims of MSBP are ominously found to have a sibling who is either deceased (25%) or to have had medical problems very similar to the current victim of the disorder (61%).

This disorder was named for Baron Karl Friedrich von Munchausen. Baron von Muchausen lived from 1720 to 1797, was born in Germany, joined the Russian military and was known to tell fantastic tales about the battles he participated in against the Ottoman Turks. For example, he apparently told stories about riding cannonballs and traveling to the moon. As opposed to MSBP, factitious disorder is a mental illness in which what are initially thought to be symptoms of illness in the sufferer are in reality a fabrication of the illness by the sufferer rather than fabrication of illness by a third person. The motivation for factitious disorder also tends to be an attempt by the sufferer to be seen as sick (assuming the sick or patient role). Emotional problems that tend to co-occur in people with MSBP include depression, anxiety, and some personality disorders like borderline personality disorder and sociopathy.

Although there is no specific cause for MSBP, like most other mental disorders, it is understood to be the result of a combination of biological vulnerabilities, ways of thinking, and social stressors (biopsychosocial model). Little is known about the specific biological vulnerabilities from which individuals with MSBP are more likely to suffer. Psychologically, MSBP perpetrators tend to have trouble forming a healthy bond (attachment) with their children. Personality traits of individuals who have a history of inducing symptoms in the children they care for include difficulty managing anger or frustration, as well as the characteristic of the perpetrator of having to overcome the urge to protect and prevent abuse of loved ones. Socially, perpetrators tend to be more likely to have suffered from some sort of major negative event (trauma) during their own childhood, including the death of a parent or having been themselves the victim of child abuse or neglect.

In the diagnostic manual that is recognized by most mental-health professionals, _The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, treatment revision_, MSBP is classified as a factitious disorder, not otherwise specified. Symptoms include the sufferer being induced to experience physical or psychological symptoms or to have symptoms fabricated by another, usually a caretaker. Specific symptoms in the victim are nearly as varied as the number of victims and perpetrators, with perhaps more emphasis on symptoms that are more feasibly manufactured or induced or are more difficult to measure objectively through laboratory tests (for example, stomach upset, other body aches and pains, trouble breathing or sleeping). Some more common symptoms presented by victims of MSBP include suffocation, induced seizures, bleeding, or poisoning that presents as vomiting or diarrhea. The abusive parent may describe symptoms in their child that do not exist. The symptoms may get worse only when the suspected caretaker is present or recently visited and may improve when the perpetrator is absent. Theories on what motivates the adult who assumes the sick role by causing a child to be sick might fall into one of three categories of motivation: help seeking, active induction of symptoms, and "addiction" to interactions with doctors. The help seeker is thought to be motivated to fabricate or cause their child's illness as a way of getting help for him or herself, assuming the sick role through their association with the supposedly sick child. This may be due to their feeling overwhelmed by their marriage, parenthood, and/or their own physical or emotional problems. The parent who actively induces symptoms of MSBP in the victim is thought to be seeking control of the medical professionals, as well as wanting recognition as an excellent parent by the professionals. Perpetrators who seem to be addicted to doctors are thought to be motivated to be seen as knowing better than the doctors.

**Muscular Atrophy, Spinal**

Spinal muscular atrophy (SMA) is a genetic disease characterized by progressive degeneration of motor neurons in the spinal cord. The disorder causes weakness and wasting of the voluntary muscles. This weakness is often more severe in the legs than in the arms.

Most of the childhood SMAs are inherited in an autosomal recessive manner. Parents usually have no symptoms but carry one copy of an SMA gene. The risk for each of their children to receive two copies of the SMA gene (onefrom each parent) and to have SMA is one-quarter.

Genes for SMA have been identified and accurate diagnostic tests exist. There are many types of SMA. Some of the more common types are described below.

**SMA type I:** Also called Werdnig-Hoffmann disease, SMA type I is evident before birth - there may be a reduction in fetal movement during the final months of pregnancy - or within the first few months of life. Symptoms include floppiness of the limbs and trunk, feeble movements of the arms and legs, swallowing and feeding difficulties, and impaired breathing. Children with SMA type I never sit or stand and usually die before the age of 2.

**SMA type II:** The disease usually becomes apparent between 3 and 15 months of age. Children with SMA type II may have respiratory problems, floppy limbs, decreased or absent deep tendon reflexes (with no kneejerk reflex), and twitching of arm, leg, or tongue muscles. These children may learn to sit but will never be able to stand or walk. Life expectancy varies.

**SMA type III:** Also called Kugelberg-Welander disease, SMA type III appears between 2 and 17 years of age with an abnormal way of walking; difficulty running, climbing steps, or rising from a chair; and slight tremor of the fingers.

**Kennedy syndrome:** Also known as progressive spinobulbar muscular atrophy, Kennedy syndrome has its clinical onset between 15 and 60 years of age. It is inherited in an X-linked recessive manner. Women carry the gene on one of their two X chromosomes, but the disorder only occurs in their sons. The risk to each son of a carrier mother is one-half to receive the gene and manifest the disease. Features may include weakness of muscles in the tongue and face, difficulty swallowing, speech impairment, and excessive development of the mammary glands in males. The disorder is slowly progressive.

**Congenital SMA with Arthrogryposis**: This is a rare disorder characterized by persistent contracture of joints (arthrogryposis) evident at birth. Features include the severe contractures, curvature of the spine, chest deformity, respiratory problems, an unusually small jaw, and drooping upper eyelids.

**Adult SMA:** This disorder may begin between 40 and 60 years of age and progresses rapidly, with an average life expectancy of about 5 years from the onset of symptoms. Most cases prove to be variants of amyotrophic lateral sclerosis (ALS, commonly called Lou Gehrig's disease). Symptoms include progressive limb weakness and weakening of the muscles, difficulty speaking and swallowing, and respiratory problems.

**What is the prognosis for SMA?**

The prognosis for individuals with SMA varies depending on the type of SMA and the degree of respiratory function. The patient's condition tends to deteriorate over time.

**What research is being done on SMA?**

Researchers have found specific genes that, when mutated, cause SMA. Several animal models of the disease have been developed as well as tests that can determine SMA gene function. This allows scientists to screen drugs that may be useful in treating SMA.

**Neuroaxonal Dystrophies**

Neuroaxonal Dystrophies is a nonspecific term referring both to the pathologic finding of swelling of distal portions of axons in the brain and to disorders which feature this finding. Neuroaxonal dystrophy is seen in various genetic diseases, vitamin deficiencies, and aging. Infantile neuroaxonal dystrophy is an autosomal recessive disease characterized by arrested psychomotor development at 6 months to 2 years of age, ataxia, brain stem dysfunction, and quadriparesis. Juvenile and adult forms also occur. Pathologic findings include brain atrophy and widespread accumulation of axonal spheroids throughout the neuroaxis, peripheral nerves, and dental pulp.

**Neuromyelitis Optica**

Neuromyelitis optica (NMO) is an uncommon disease syndrome of the central nervous system (CNS) that affects the optic nerves and spinal cord.

Individuals with neuromyelitis optica develop optic neuritis, which causes pain in the eye and vision loss, and transverse myelitis, which causes weakness, numbness, and sometimes paralysis of the arms and legs, along with sensory disturbances and loss of bladder and bowel control. Neuromyelitis optica leads to loss of myelin, which is a fatty substance that surrounds nerve fibers and helps nerve signals move from cell to cell. The syndrome can also damage nerve fibers and leave areas of broken-down tissue. In the disease process of neuromyelitis optica, for reasons that aren't yet clear, immune system cells and antibodies attack and destroy myelin cells in the optic nerves and the spinal cord.

Historically, neuromyelitis optica was diagnosed in patients who experienced a rapid onset of blindness in one or both eyes, followed within days or weeks by varying degrees of paralysis in the arms and legs. In most cases, however, the interval between optic neuritis and transverse myelitis is significantly longer, sometimes as long as several years. After the initial attack, neuromyelitis optica follows an unpredictable course. Most individuals with the syndrome experience clusters of attacks months or years apart, followed by partial recovery during periods of remission. This relapsing form of neuromyelitis optica primarily affects women. The female to male ratio is greater than 4:1. Another form of neuromyelitis optica, in which an individual only has a single, severe attack extending over a month or two, is most likely a distinct disease that affects men and women with equal frequency. The onset of neuromyelitis optica varies from childhood to adulthood, with two peaks, one in childhood and the other in adults in their 40s.

In the past, neuromyelitis optica was considered to be a severe variant ofmultiple sclerosis (MS) because both can cause attacks of optic neuritis and myelitis. Recent discoveries, however, suggest it is a separate disease. Neuromyelitis optica is different from MS in the severity of its attacks and its tendency to solely strike the optic nerves and spinal cord at the beginning of the disease. Symptoms outside of the optic nerves and spinal cord are rare, although certain symptoms, including uncontrollable vomiting and hiccups, are now recognized as relatively specific symptoms of neuromyelitis optica that are due to brainstem involvement.

The recent discovery of an antibody in the blood of individuals with neuromyelitis optica gives doctors a reliable biomarker to distinguish neuromyelitis optica from MS. The antibody, known as NMO-IgG, seems to be present in about 70 percent of those with neuromyelitis optica and is not found in people with MS or other similar conditions.

**Neuronal Ceroid-Lipofuscinoses**

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of neurodegenerative disorders. They are considered the most common of the neurogenetic storage diseases with a prevalence of 1 in 12,500 in some populations. They are associated with variable yet progressive symptoms including seizures, dementia, visual loss, and/or cerebral atrophy. In 1826, Stengel described the first patients—4 siblings in Norway. Batten made the first clinicopathologic correlation in 1903 and referred to NCL as familial cerebromacular degeneration. Batten was also the first person to differentiate NCL from Tay-Sachs disease in 1914. Vogt, Spielmeyer, Bielschowsky, and Kufs also described older patients with similar symptoms.

In 1939, Klenk discovered increased gangliosides in Tay-Sachs disease but in not juvenile amaurotic idiocy (an early name for NCL). NCL was later so named because of the accumulation of autofluorescent lipopigments resembling ceroid and lipofuscin. In 1959, Koppang described English setters with the same phenotype as patients with NCL. Although NCLs are generally autosomal recessive disorders, in 1971 Boehme also described autosomal dominant inheritance of the same disease in the Parry family of New Jersey. The enzymatic abnormalities were better defined in the 1980s and the molecular genetics have now being described in some variants of NCL.

The NCLs are almost all characterized by apoptosis and dysregulated sphingolipid metabolism. It is suspected that there are common pathways for many of the variants. Persaud-Sawin et al found that transfecting CLN1 or CLN2 deficient cells with CLN DNA constructs for either CLN1 or CLN2 was somewhat protective against etoposide-induced apoptosis in both cells types. CLN6 and CLN8 constructions resulted in near total correction of growth defects in CLN3 deficient cells and CLN2 DNA constructs were partially effective. CLN2, CLN3, and CLN8 constructs corrected growth for CLN6 deficient cells. CLN2, CLN3, and CLN6 constructs also corrected growth for CLN8 deficient cells.[2]

In CLN1, a lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1) is deficient. PPT1, which removes fatty acyl groups from cysteine residues on fatty acid modified proteins, remains in the endoplasmic reticulum where it is inactive, causing sapsosins A and D to accumulate in the lysosomes. Mutations have been found in all 9 exons of the _CLN1_ gene. Although CLN1 usually had onset in infancy, later onset (including in adulthood) has also been described. More than 49 mutations have been described in _CLN1_. Lyly et al found that glycosylation of N197 and N232, but not N212 is essential for PPT1s activity and intracellular transport. They also found that PPT1 formed oligomers. They believe that mutations cause more glycosylation and complex formation.[3]

Subunit C of the mitochondrial ATP synthase complex accumulates in the lysosomes of patients with some variants of NCL, including CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, and CLN8. Subunit C also accumulates in some animal models of NCL, including the bovine and several canine variants. Subunit C, an extremely hydrophobic 75-amino-acid protein, is encoded by 2 separate genes, _P1_and _P2.P1_ is on chromosome 17 and _P2_ is on chromosome 12. The mRNA for _P2_is the predominant form. Subunit C is part of a transmembrane proton channel located on the inner mitochondrial membrane. Each ATP synthase complex has 10-12 copies of subunit C.

Patients with CLN2 are deficient in a pepstatin-insensitive lysosomal peptidase—tripeptidyl peptidase 1 (TTP1). TTP1 removes tripeptides from the _N_ -terminal of polypeptides. Mutations have been reported in all 13 exons of the _CLN2_ gene. Some mutations result in a more protracted course. Although onset is usually in late infancy, later onset has been described. More than 58 mutations have been described in _CLN2_.[1]

The _CLN3_ gene encodes a 438 amino acid protein that is thought to be a part of the lysosomal membrane. The most common mutation of _CLN3_ is a 1.02-kb deletion that involves loss of exons 7 and 8. Most patients with the classic phenotype of JNCL are homozygous for the 1.02-kb deletion. Patients who are compound heterozygotes for this deletion may have atypical phenotypes. Munroe reported 2 patients who were compound heterozygotes with visual failure, only one of whom had seizures; both patients were able to hold full-time employment as adults. Wisniewski et al reported similar patients who initially presented with psychiatric or behavioral symptoms but otherwise had a typical course. More than 42 mutations have been described in _CLN3_. The exact function of _CLN3_ is unknown, but its expression is highest in secretory/glandular tissues and in gastrointestinal cells. All patients with CLN3 have had visual failure by age 10.

The adult form of NCL (ANCL) is associated with mutations of the _CLN4_ gene. The_CLN4_ gene has not been mapped yet.

Mutations in another gene, _CLN5_ is associated with Finnish variant LINCL (fLINCL). It occurs predominantly in the Finnish population. _CLN5_ encodes a 407 amino acid transmembrane protein. CLN5 only occurs in vertebrae. The expression of _CLN5_ increases during cortical neurogenesis. More than 17 mutations have been described in _CLN5_.[1]

The _CLN6_ gene is associated with variant LINCL (vLINCL). Disease caused by_CLN6_ mutations are also referred to as the Czech or Indian variant. The _CLN6_ gene has been mapped to band 15q21-q23 and encodes a 311 amino acid membrane protein. More than 36 mutations have been described in _CLN6_. Affected individuals with CLN6 mutations are primarily of Portuguese, Indian, Pakistani, or Czech ancestry.

The _CLN7_ gene has been assigned to the tLINCL variant. Individuals with the tLINCL variant were thought to originate from Turkey. Siintola et al identified 6 mutations in 5 families, 4 Turkish families and 1 Indian family, in the _MFSD8_ gene. The authors mapped the locus to 4q28.1-q28.2. The gene encodes a 518 amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 localizes mainly to the lysosomal compartment and is ubiquitously disease-causing mutations have been identified.[1]

_CLN8_ encodes a 286 amino acid transmembrane protein, which localizes to the endoplasmic reticulum and endoplasmic reticulum-Golgi intermediate complex. The exact function of the CLN8 protein is unknown. More than 11 mutations have been described in _CLN8._ Some mutations cause vLINCL, but missense mutations (c.70CG for 24Gly and c.709GA for 237Arg in association with c.70CG) can also result in progressive epilepsy with mental retardation (PEMR) or Northern epilepsy, which is a protracted disease.

Schulz et al reported that _CLN9_ produces a protein that may be a regulator of dihydroceramide synthetase. Even though the CLN8 sequence was normal, transfection with CLN8 corrected growth and apoptosis in CLN9 deficient cells.

Two putative disease-causing mutations have also been identified for CLCN6.[1]

**Niemann-Pick Diseases**

Niemann-Pick disease is a biochemical disorder affecting a lipid (fat) called sphingomyelin, resulting usually in progressive enlargement of the liver and spleen (hepatosplenomegaly), "swollen glands" (lymphadenopathy), anemia and mental and physical deterioration. Niemann-Pick disease is hereditary and follows an autosomal recessive pattern.

The classical form of the disease is Niemann-Pick disease type A. Its onset is in very early infancy and death is usually before age 3. The lipid accumulates in cells (called reticuloendothelial cells) in the liver and spleen and in other types of cells throughout the body including the nerve ganglion cells of the central nervous system. The neurological features include mental retardation, spasticity, seizures, jerks, eye paralysis (ophthalmoplegia) and ataxia (wobbliness). Physical growth is retarded. The gastrointestinal features include hepatosplenomegaly, jaundice, hepatic (liver) failure, and ascites (fluid in the abdomen). Eye hallmarks of Niemann-Pick disease include the "cherry red spot" in the macula in the center of the retina, opacity of the cornea and brown discoloration of the lens capsule. Respiratory problems include pulmonary infiltration. Coronary artery disease occurs early. There is easy bruising. Typical cells (called Niemann-Pick cells) that have a foamy appearance due to their storage of sphingomyelin are found in the bone marrow, spleen and lymph nodes. These unusual cells help in establishing the diagnosis. The sphingomyelin accumulation is due to deficiency of the enzyme sphingomyelinase. The gene for this enzyme and hence the location of the gene for Niemann-Pick disease type A is in chromosome band 11p15.4-p15.1.

At least 5 forms of Niemann-Pick disease have been distinguished: the classical infantile form (type A), the visceral (organ) form (type B), the subacute or juvenile form (type C), the Nova Scotian variant (type D), and the adult form (type E).

The disease is named for the German physicians Albert Niemann (1880-1921) and Ludwig Pick (1868-1944). Other names for the disease include sphingomyelin lipoidosis and sphingomyelinase deficiency.

Niemann-Pick disease type C, abbreviated NPC, is a type of Niemann-Pick disease inherited in an autosomal recessive manner, resulting in lipid storage in the brain and body. At the cellular level, the disorder is characterized by the accumulation of cholesterol and glycolipid. Most (about 95%) of NPC patients have mutations in the NPC1 gene in chromosome 18q11 which encodes a large membrane glycoprotein. The rest (about 5%) of NPC patients have mutations in the NPC2 gene in chromosome 14q24.3 which encodes a small cholesterol-binding protein. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggest that the two NPC proteins function in a coordinate fashion in the cellular transport of cholesterol, glycolipids and other cargo.

**Noonan Syndrome**

Noonan syndrome is a developmental disorder characterized by unusual facial characteristics, short stature, heart defects, bleeding problems, and skeletal malformations. Eye abnormalities occur in up to 95 percent of people with Noonan syndrome. Problems with language and speech are common. Puberty for both males and females with Noonan syndrome is usually delayed for approximately two years. Most males with this disorder have undescended testicles (cryptorchidism) which can lead to infertility (inability to father a child) later in life. The majority of children diagnosed with Noonan syndrome have normal intelligence, but a small percentage have special educational needs, and some have mental retardation.

Noonan syndrome occurs in approximately 1 in 1,000 to 2,500 people.

Mutations in the KRAS, PTPN11, RAF1, and SOS1 genes cause Noonan syndrome.

Approximately 50 percent of individuals with Noonan syndrome have mutations in the PTPN11 gene. Mutations in the SOS1 gene are seen in 20 percent of those with Noonan syndrome. Mutations in the RAF1 gene account for between 10 and 15 percent of Noonan syndrome cases. About 5 percent of people with Noonan syndrome have mutations in the KRAS gene and usually have a more severe or atypical form of the disorder. The cause of Noonan syndrome in the remaining 10 to 15 percent of people with this disorder is unknown.

The PTPN11, SOS1, KRAS, and RAF1 genes all provide instructions for making proteins that are important for the proper formation of several types of tissue during development. These proteins also play roles in cell division, cell movement, and cell differentiation (the process by which cells mature to carry out specific functions).

Mutations in the PTPN11 gene, SOS1 gene, KRAS gene, or RAF1 gene cause the resulting protein to be continuously active, rather than switching on and off in response to signals that control growth and development. This constant activation disrupts the regulation of systems that control cell growth and division, leading to the characteristic features of Noonan syndrome.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

**Optic Atrophies, Hereditary**

Optic Atrophies, Hereditary are hereditary conditions that feature progressive visual loss in association with optic atrophy. Relatively common forms include autosomal dominant optic atrophy (OPTIC ATROPHY, AUTOSOMAL DOMINANT) and Leber hereditary optic atrophy (OPTIC ATROPHY, HEREDITARY, LEBER).

Leber's Hereditary Optic Atrophies is an inherited eye disorder characterized by progressive loss of central vision caused by degeneration of the optic nerves and retina. Vision can be lost very quickly or can happen gradually over a few years. The condition is more common in males than females.

The list of signs and symptoms mentioned in various sources for Leber's hereditary optic atrophy includes the 1 symptoms listed below:

Progressive visual impairment

**Osteitis Deformans**

**Osteitis deformans:** Better known today as Paget disease, this is a chronic bone disorder that typically results in enlarged, deformed bones due to excessive breakdown and formation of bone tissue that can cause bones to weaken and may result in bone pain, arthritis, bony deformities and fractures. The disease is named for an English surgeon, Sir James Paget (1814-1899).

Paget disease is rarely diagnosed in people under 40. Men and women are affected equally. Because Paget disease may be familial, after age 40, brothers, sisters and children of someone with Paget disease may wish to have an alkaline phosphatase blood test every 2 or 3 years to screen for Paget disease.

Many people do not know they have Paget disease because they have a mild case of the disease with no symptoms. Sometimes, symptoms may be confused with those of arthritis or other disorders. The symptoms of Paget disease can include:

Bone pain - the most common symptom. Bone pain can occur in any bone affected by Paget's disease. It often localizes to areas adjacent to the joints.

Headaches and hearing loss - may occur when Paget's disease affects the skull.

Pressure on nerves - may occur when Paget's disease affects the skull or spine.

Increased head size, bowing of limb, or curvature of spine - may occur in advanced cases.

Hip pain - may occur when Paget's disease affects the pelvis or thighbone.

Damage to cartilage of joints - may lead to arthritis.

Paget disease may be diagnosed using one or more of the following tests:

X-rays - Pagetic bone has a characteristic appearance on x-rays.

Alkaline phosphatase test - An elevated level of alkaline phosphatase in the blood can be suggestive of Paget disease.

Bone scan - Useful in determining the extent and activity of the condition. If a bone scan suggests Paget disease, the affected bone or bones should be x-rayed to confirm the diagnosis.

The outlook with Paget disease is generally good, particularly if treatment is given before major changes have occurred in the affected bones. Paget disease occurs most frequently in the spine, skull, pelvis, thighs, and lower legs. In general, symptoms progress slowly, and the disease does not spread to normal bones. Treatment can control Paget disease and lessen symptoms but is not a cure.

Paget's disease may lead to other medical conditions, including:

Arthritis - Long bones in the leg may bow, distorting alignment and increasing pressure on nearby joints. In addition, Pagetic bone may enlarge, causing joint surfaces to undergo excessive wear and tear. In these cases, pain may be due to a combination of Paget disease and osteoarthritis.

Hearing - Loss of hearing in one or both ears may occur when Paget disease affects the skull and the bone that surrounds the inner ear. Treating the Paget disease may slow or stop hearing loss. Hearing aids may also help.

Heart disease - In severe Paget disease, the heart works harder to pump blood to affected bones. This usually does not result in heart failure except in some people who also have hardening of the arteries.

Kidney stones - Kidney stones are somewhat more common in patients with Paget disease.

Nervous system - Pagetic bone can cause pressure on the brain, spinal cord, or nerves, and reduced blood flow to the brain and spinal cord.

Sarcoma - Rarely, Paget disease is associated with the development of osteosarcoma, a malignant tumor of bone. When there is a sudden onset or worsening of pain, sarcoma should be considered.

Teeth - When Paget disease affects the facial bones, the teeth may become loose. Disturbance in chewing may occur.

Vision-Rarely, when the skull is involved, the nerves to the eye may be affected, causing some loss of vision.

Paget disease is NOT associated specifically with osteoporosis. Although Paget disease and osteoporosis can occur in one and the same person, they are completely different disorders. But, despite their marked differences, many treatments for Paget disease can also be used to treat osteoporosis.

The goal of drug treatment is to control Paget disease activity for as long a period of time as possible. Treatment options include aspirin, other anti-inflammatory medications, pain medications, and medications that slow the rate of bone turnover, such as calcitonin (Calcimar, Miacalcin) and the bisphosphonates including etidronate (Didronel), alendronate (Fosamax), pamidronate (Aredia), tiludronate (Skelid), and risedronate (Actonel).

There are generally three major complications of Paget disease for which surgery may be recommended.

Fractures - Surgery may allow fractures to heal in better position.

Severe degenerative arthritis - If disability is severe and medication and physical therapy are no longer helpful, joint replacement of the hips and knees may be considered.

Bone deformity - Cutting and realignment of Pagetic bone (osteotomy) may help painful weight-bearing joints, especially the knees.

Complications resulting from enlargement of the skull or spine may injure the nervous system. However, most neurologic symptoms, even those that are moderately severe, can be treated with medication and do not require neurosurgery.

In general, people with Paget's disease should receive 1000-1500 mg of calcium, adequate sunshine, and at least 400 units of vitamin D daily. This is especially important in patients being treated with bisphosphonates. Patients with a history of kidney stones should discuss calcium and vitamin D intake with their physician.

Exercise is very important in maintaining skeletal health, avoiding weight gain, and maintaining joint mobility. Since undue stress on affected bones should be avoided, patients should discuss any exercise program with their physician before beginning.

**Osteochondritis**

Osteochondritis dissecans facts

Osteochondritis dissecans is a joint condition whereby a variable amount of bone and its adjacent cartilage loses its blood supply.

The cause of osteochondritis dissecans is often unknown.

Symptoms include joint pain, stiffness, and even locking of the joint.

Osteochondritis dissecans is best diagnosed with imaging studies.

Arthroscopic surgery is a procedure that is frequently used as a treatment to remove the loose cartilage and bone tissue from the joint.

Osteochondritis dissecans is a joint condition whereby a variable amount of bone and its adjacent cartilage loses its blood supply. Osteochondritis dissecans can involve the bone and cartilage of virtually any joint. Elbows and knees are most commonly affected. Usually, only a small portion of the affected cartilage is involved. Osteochondritis dissecans most commonly affects boys between 9 and 18 years of age.

The cause of osteochondritis dissecans is often unknown. Theories include mild recurrent injuries or growth disturbances.

Symptoms of osteochondritis dissecans are a direct result of the irregularity of the cartilage within the affected joint. Symptoms include joint pain, stiffness, and even locking of the joint so that its range of motion is significantly limited to the point that it cannot be moved beyond a limited range. For example, when osteochondritis dissecans affects the elbow, the joint may not move beyond 90 degrees of extension instead of being able to fully extend straight to 180 degrees.

**Osteochondrodysplasias**

Hypertrichotic osteochondrodysplasia is a rare syndrome characterized by mental retardation, short stature, large skull, heart anomaly and various other abnormalities.

The list of signs and symptoms mentioned in various sources for Hypertrichotic osteochondrodysplasia includes the 40 symptoms listed below:

Growth of excess hair

Enlarged heart

Wide ribs

Narrow thorax

Coxa valga

Flattened spine bones

Reduced bone mineral density

Large birth weight

Large birth size

Coarse face

Large skull

Prominent forehead

Long upper lip groove

Long curly eyelashes

Anteverted nostrils

Epicanthal folds

Flat nose bridge

Broad nose bridge

Thick lips

Enlarged bums

Short neck

Congenital enlargement of left heart ventricle

Pericardial effusion

Bicuspid aortic valve

Patent ductus arteriosus

Narrow chest

Narrow shoulder

Umbilical hernia

Osteoporosis

Delayed bone age

Flattened vertebrae

Abnormal vertebral shape

Wide bone metaphyses

Abnormal bone growth

Erlenmeyer flask shaped long bones

Short big toe

Broad big toe

Lymphedema

Excessive hairiness

Mental retardation - mild

To research the causes of Hypertrichotic osteochondrodysplasia, consider researching the causes of these these diseases that may be similar, or associated with Hypertrichotic osteochondrodysplasia:

Mental retardation

Large skull

Heart anomaly

Short stature

**Paget's Disease, Mammary**

Paget's disease is a special type of breast cancer.

The list of signs and symptoms mentioned in various sources for Paget's Disease includes the 18 symptoms listed below:

Itchy nipple

Sore nipple

Itchy areola

Sore areola

Cracked nipple

Weeping nipple

Crusting over of nipple

Fissured areola of nipple

Nipple ulceration

Oozing nipples

Hyperemia

Nipple retraction

Moist red skin

Eczema-like lesions

Crusted lesions

Redness of the nipple

Crusting of the nipple skin

Symptoms of more advanced disease often include tingling, itching, increased sensitivity, burning, or pain in the nipple

**Papillon-Lefevre Disease**

Papillon-Lefevre syndrome (PLS) is a rare ectodermal dysplasia characterized by palmoplantar keratoderma associated with early-onset periodontitis.

The prevalence is estimated between 1/250,000 and 1/1,000,000 individuals. The male to female ratio is 1:1. PLS is found in all ethnic groups.

Diffuse palmoplantar keratoderma (PPK) with erythematous plaques develops between the first and fourth years of life, with the soles being usually more severely affected than the palms. Psoriasiform hyperkeratosis can overflow onto the dorsal surfaces of the hands and feet (transgredient spread) and, less frequently, lesions can be seen on the limbs (knees, elbows). Skin lesions are followed by intense gingivitis that rapidly progresses into periodontitis with alveolar bone lysis and early loss of primary dentition. The skin lesions are aggravated by cold and during episodes of severe periodontitits. During childhood, the phenomenon of periodontal disease recurs with rapid loss of permanent dentition. Cases of PLS with mild and/or late-onset periodontal disease have been reported occasionally. PLS is accompanied, in half of the patients, by enhanced susceptibility to cutaneous and systemic infections (furunculosis, skin abscesses, pyoderma, hidradenitis suppurativa, respiratory tract infection...). Patients may also present with malodorous hyperhidrosis, follicular hyperkeratosis, nail dystrophy or dural calcifications. The association of PLS with malignant melanoma or squamous cell carcinoma has been reported in very rare occasions.

PLS is due to mutations in the _CTSC_ gene (11q14-q21) that codes for cathepsin C (also known as dipeptidyl peptidase I), a lysosomal protease playing a role in epidermal differentiation and desquamation and in activation of serine proteases expressed in cells of the immune system. _CTSC_ mutations lead to an almost total loss of cathepsin C activity which seems to result in susceptibility to specific virulent pathogens. It is also suggested that other immune-mediated deficiencies in the host defense mechanism could be involved in the pathogenesis of PLS.

Diagnosis is based on clinical signs. Dental radiography shows atrophy of the alveolar bone. Neutrophil function tests reveal anomalies of chemotaxis and phagocytosis by polymorphonuclear leukocytes. Skin biopsy shows hyperkeratosis with focal parakeratosis, moderate perivascular infiltration, hypergranulosis, and acanthosis. Biochemical analysis reveals a loss of CTSC activity. Diagnosis is confirmed by genetic testing.

Differential diagnosis includes two rare disorders that are allelic variants of PLS, Haim-Munk syndrome and prepubertal/aggressive periodontitis (see this term). Other diseases with similar dermatologic features include localized epidermolytic palmoplantar keratoderma (Vörner), mal de Meleda, Howel-Evans syndrome, keratosis punctata, and Greither's disease (see these terms).

Antenatal diagnosis is theoretically possible but has never been reported.

Transmission is autosomal recessive. Genetic counseling should be offered to the parents of an affected individual informing them of the 25% chance their offspring has of inheriting the disease causing mutation.

Treatment is based on oral retinoids which attenuate the palmoplantar keratoderma and slow the alveolar bone lysis. Antibiotics, along with oral hygiene and use of mouth rinses, are also recommended for slowing the progression of periodontitis. Ultimately, primary or remaining teeth are extracted and are replaced by dental implants. Antibiotherapy is also used in the treatment of recurrent infections. Etretinate (a synthetic retinoid of acitretin) shows promising results in the treatment of PLS.

Despite meticulous dental care, all patients eventually become edentous at the beginning of adulthood. Life expectancy is normal.

**Pelizaeus-Merzbacher Disease**

Pelizaeus-Merzbacher disease is a disorder of the central nervous system (CNS) in which there is loss of myelin, the sheath around the nerves. The disease is clinically characterized by nystagmus (rhythmical oscillation of the eyes), impaired motor development, tremor, progressive spasticity (increased muscle tone), ataxia (wobbliness), choreoathetotic movements, and dysartria (difficulty speaking). Pelizaeus-Merzbacher disease (PMD) in its classical form manifests in infancy or early childhood and progresses to severe spasticity and ataxia. The lifespan may be shortened.

PMD is due to mutation in the gene PLP1. This gene is located on the X chromosome in band Xq22. The disease describes an X-linked pattern of inheritance with boys who have the mutation affected with the disease while females with the mutation are carriers.

The PLP1 gene encodes proteolipid protein (PLP), the most abundant protein of the myelin sheath in the CNS. The mutation in PLP1 in PMD results in loss of myelin and that, in turn, causes the neurological abnormalities.

The severity of myelin loss is dependent on the particular PLP1 mutation and can range from early lethal forms of PMD to a mild disorder known as spastic paraplegia type 2 (SPG2).

Among the mutations in the PLP1 gene locus that can cause PMD is a duplication of PLP1 in which the duplicated region may be far away from the original PLP locus in chromosome region Xq22. The PLP1 duplication is almost always present in the mothers of affected boys and usually can be traced to the maternal grandfather.

The disease is named for the German neurologist Friedrich Pelizaeus (1850-1917) and psychiatrist Ludwig Merzbacher (1875-1942) who independently described the disorder in 1885 and 1909, respectively. The disease is a hypomyelinating X-linked leukodystrophy.

**Pemphigus, Benign Familial**

Benign chronic familial pemphigus of Hailey-Hailey is characterized by rhagades mostly located in the armpits, inguinal and perineal folds (scrotum, vulva). Prevalence is unknown. Skin lesions appear during adolescence or more often at the age of 30-40 years; they are relapsing and recurrent. Lesions can be complicated by heat, rubbing or superinfections. Benign chronic familial pemphigus is transmitted as a dominant trait, with incomplete penetrance. Mutations in the _ATP2C1_ gene (localised to 3q21-q24), encoding a calcium pump, cause the disease by impairing epidermal keratinocyte adhesion. Histopathological analysis of the lesions shows suprabasal acantholysis of epidermal cells. There is no specific treatment, but drying the affected areas is essential as well as employing measures to prevent bacterial, fungal and viral infections. Topical medical treatment can alleviate the symptoms in milder forms. Physical treatments are very effective for more severe forms: CO2 laser therapy (pulse or continuous) is often proposed as a first-line treatment. Other techniques, such as dermabrasion or excision-graft, may also be required to correct the symptoms of this dermatosis.

**Penile Induration**

**Penile Induration**: A condition characterized by hardening of the penis due to the formation of fibrous plaques on the dorsolateral aspect of the penis, usually involving the membrane (tunica albuginea) surrounding the erectile tissue (corpus cavernosum penis). This may eventually cause a painful deformity of the shaft or constriction of the urethra, or both.

**Pericarditis, Constrictive**

**Constrictive pericarditis:** Scarring of the pericardial sac. This limits the ability of the heart to function because it cannot expand enough to collect blood and pump it to the lungs and then back to the body. Bleeding into the pericardium from trauma or from a heart operation is the most common cause of constrictive pericarditis, but tumors or infections can also be the cause. The constriction occurs slowly over time and causes shortness of breath on exertion and a decreased ability to exercise. Swelling in the legs and the abdomen may exist because it is difficult for blood to return to the heart, and fluid leaks out into the tissues. Pericardotomy, an operation to split open the pericardium to free up the constriction around the heart, may be required to improve function.

**Peroxisomal Disorders**

Peroxisomal disorders are a group of congenital diseases characterized by the absence of normal peroxisomes in the cells of the body.

Peroxisomes are organelles within a cell that contain enzymes responsible for critical cellular processes. A cell can contain several hundred peroxisomes, round or oval bodies with diameters of about 0.5 micron that contain proteins that function as enzymes in metabolic processes. By definition, a peroxisome must contain catalase, which is an enzyme that breaks down hydrogen peroxide.

Peroxisomal disorders are subdivided into two major categories: those disorders resulting from a failure to form intact, normal peroxisomes, resulting in multiple metabolical abnormalities, which are referred to as peroxisome biogenesis disorders (PBD) or generalized peroxisomal disorders; and those disorders resulting from the deficiency of a single peroxisomal enzyme. There are about 25 known peroxisomal disorders, although the number of diseases that are considered to be separate, distinct peroxisomal disorders varies among researchers and healthcare practitioners.

Approximately 50 different biochemical reactions occur entirely or partially within a peroxisome. Some of the processes are anabolic (constructive), resulting in the synthesis of essential biochemical compounds, including bile acids, cholesterol, plasmalogens, and docosahexanoic acid (DHA), which is a long chain fatty acid that is a component of complex lipids, including the membranes of the central nervous system. Other reactions are catabolic (destructive) and lead to the destruction of some fatty acids, including very long chain fatty acids (VLCFAs, fatty acids with more than 22 carbon atoms in their chains), phytanic acid, pipecolic acid, and the prostoglandins. The peroxisome is involved in breaking down VLCFAs to lengths that the body can use or get rid of.

When VLCFAs accumulate due to abnormal functioning of the peroxisomes, they are disruptive to the structure and stability of certain cells, especially those associated with the central nervous system and the myelin sheath, which is the fatty covering of nerve fibers. The peroxisomal disorders that include effects on the growth of the myelin sheath are considered to be part of a group of genetic disorders referred to as leukodystrophies.

Peroxisomal disorders form a heterogeneous disease group, with different degrees of severity. The differences among these disorders are continuous, with overlap between abnormalities. Examples of peroxisomal disorders are:

X-linked adrenoleukodystrophy (X-ALD), a sex-linked disorder characterized by progressive symptoms that begin as behavioral changes, muscle weakness, and speech difficulties.

Zellweger syndrome (ZS), which is usually fatal within the first year of life.

Neonatal adrenoleukodystrophy (NALD), which is usually fatal within the first ten years.

Infantile Refsum disease (IRD), which is not as devastating as ZS and NALD, as the children with this disorder with time and patience can develop some degree of motor, cognitive, and **communication skills**, although death generally occurs during the second decade of life.

Rhizomelic chondrodysplasia punctata (RCDP), which in its most severe form is fatal within the first year or two of life; however, survival into the teens has been known to occur. It is characterized by shortening of the proximal limbs (i.e., the legs from knee to foot and the arms from elbow to hand).

Zellweger-like syndrome, which is fatal in infancy and known to be a defect of three particular enzymes.

Most peroxisomal disorders are inherited autosomal recessive diseases. This means that both parents need to be carriers of the defective gene in order for a child to develop the disease. If both parents are carriers but do not show signs of disease, each child has a 25 percent chance of having the disease. If one parent has the disease and the other is a carrier, each child has a 50 percent chance of having the disease. As a sex-linked genetic disorder, the daughters of males affected with X-ALD become carriers and the sons are not affected. The children of female carriers have a 50 percent chance of having the genetic mutation, which means that sons who inherit the mutation have the disease, and daughters who inherit the mutation are carriers.

Peroxisomal disorders occur in all countries, among all races and ethnic groups. They are extremely rare, with frequencies reported at one in 30,000 to one in 150,000, although these numbers are only estimates. X-ALD is the most common of the peroxisomal disorders, affecting about one in 20,000 males. It is estimated that there are about 1,400 people in the United States with the disorder. ZS is estimated to affect one in 50,000 to 100,000 live births.

The range of disease abnormalities may be a result of a corresponding range of peroxisome failure. For example, in severe cases of ZS, the failure is nearly complete, while in IRD, there is some degree of peroxisome activity. In peroxisomal single-enzyme disorders, the peroxisome is intact and functioning, but there is a defect in only one enzymatic process, with only one corresponding biochemical abnormality. These disorders, however, can be as severe as those in which peroxisomal activity is nearly or completely absent.

In general, **developmental delay**, **mental retardation**, and vision and **hearing impairment**are common in those who have these disorders. Acquisition of speech appears to be especially difficult, and because of the reduced communication abilities, **autism**is common in those who live longer. Peroxisomal disorder patients have decreased muscle tone (**hypotonia**), which in the most severe cases is generalized, while in less severe cases, is usually restricted to the neck and trunk muscles. Sometimes this lack of control is only noticeable by a curved back in the sitting position. Head control and independent sitting is delayed, with most patients unable to walk independently.

**Failure to thrive**is a common characteristic of patients with peroxisomal disorder, along with an enlarged liver, abnormalities in liver enzyme function, and loss of fats in stools (steatorrhea). Peroxisomal disorders are also associated with facial abnormalities, including high forehead, frontal bossing (swelling), small face, low set ears, and slanted eyes. These characteristics may not be prominent in some children and are especially difficult to identify in an infant.

In X-ALD there is a deficiency in the enzyme that breaks down VLCFAs, which then accumulate in myelin and the adrenal glands. Onset of X-ALD-related neurological symptoms occurs at about five to 12 years of age, with death occurring within one to ten years after onset of symptoms. In addition to physical abnormalities seen in other types of peroxisomal disorders, common symptoms of X-ALD also include behavioral changes such as abnormal withdrawal or aggression, poor memory, dementia, and poor academic performance. Other symptoms are muscle weakness and difficulties with hearing, speech, and vision. As the disease progresses, muscle tone deteriorates, swallowing becomes difficult, and the patient becomes comatose. Unless treated with a diet that includes a mixture of oils called Lorenzo's oil, the disease will result in paralysis, hearing loss, blindness, vegetative state, and death. There are also milder forms of X-ALD, an adult onset ALD that typically begins between the ages of 21 and 35, and a form that is occasionally seen in women who are carriers of the disorder. In addition to X-ALD, there are at least ten other single-enzyme peroxisomal disorders, each with its own specific abnormalities.

**Adrenal glands**—A pair of endocrine glands (glands that secrete hormones directly into the bloodstream) that are located on top of the kidneys. The outer tissue of the glands (cortex) produces several steroid hormones, while the inner tissue (medulla) produces the hormones epinephrine (adrenaline) and norepinephrine.

**Autosomal recessive mutation**—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

**Autosome**—A chromosome not involved in sex determination.

**Enzyme**—A protein that catalyzes a biochemical reaction without changing its own structure or function.

**Fontanelle**—One of several "soft spots" on the skull where the developing bones of the skull have yet to fuse.

**Organelle**—A specialized structure within a cell, which is separated from the rest of the cell by a membrane composed of lipids and proteins, where chemical and metabolic functions take place.

**Peutz-Jeghers Syndrome**

Peutz-Jeghers syndrome is a cancer genetic disorder characterized by freckle-like spots on the lips, mouth and fingers and polyps in the intestines. Patients are at increased risk for developing cancer of the esophagus, stomach, colon, rectum, breast, ovary, testis and pancreas.

The polyps may occur in any part of the gastrointestinal tract, but polyps in the jejunum (the middle portion of the small intestine) are a consistent feature of the disease. Intussusception (telescoping of the bowel) and intestinal bleeding are also common symptoms.

Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign tumor of the ovary. Males may develop Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia (male breast enlargement). Females can also have a malignancy of the cervix called adenoma malignum.

Peutz-Jeghers syndrome is inherited in an autosomal dominant manner and is due to mutation in a gene on chromosome 19p13.3 called STK11 (serine/threonine-protein kinase 11) that appears to function as a tumor suppressor gene. Half of patients have an affected parent from whom they inherited an STK11 mutation and the other half have a new mutation in the STK11 gene.

The risk of cancer in the Peutz-Jeghers syndrome is very high. Among 210 patients with the symdrome, the risk of developing noncutaneous cancer between the ages of 15 to 64 was 93%. The highest cumulative risks were for breast cancer (54%), colon cancer (39%), pancreatic cancer (36%), stomach cancer (29%), and ovarian cancer (21%).

In 1921 Peutz was the first to recognize the familial association of gastrointestinal polyps and spots. A review by Jeghers et al. in The New England Journal of Medicine in 1949 put the polyps-and-spots syndrome "on the map."

**Pick Disease of the Brain**

Frontotemporal dementia (FTD) describes a clinical syndrome associated with shrinking of the frontal and temporal anterior lobes of the brain. Originally known as Pick's disease, the name and classification of frontotemporal dementia has been a topic of discussion for over a century. The current designation of the syndrome groups together Pick's disease, primary progressive aphasia, and semantic dementia as FTD. Some doctors propose adding corticobasal degeneration and progressive supranuclear palsy to frontotemporal dementia and calling the group Pick Complex. These designations will continue to be debated.

As it is defined today, the symptoms of frontotemporal dementia fall into two clinical patterns that involve either (1) changes in behavior, or (2) problems with language.

The first type features behavior that can be either impulsive (disinhibited) or bored and listless (apathetic) and includes:

inappropriate social behavior;

lack of social tact;

lack of empathy;

distractibility;

loss of insight into the behaviors of oneself and others;

an increased interest in sex;

changes in food preferences;

agitation or, conversely, blunted emotions;

neglect of personal hygiene;

repetitive or compulsive behavior; and

decreased energy and motivation.

The second type primarily features symptoms of language disturbance, including difficulty making or understanding speech, often in conjunction with the behavioral type's symptoms. Spatial skills and memory remain intact.

There is a strong genetic component to the disease; frontotemporal dementia often runs in families.

No treatment has been shown to slow the progression of frontotemporal dementia. Behavior modification may help control unacceptable or dangerous behaviors. Aggressive, agitated, or dangerous behaviors could require medication. Anti-depressants have been shown to improve some symptoms.

The outcome for people with frontotemporal dementia is poor. The disease progresses steadily and often rapidly, ranging from less than 2 years in some individuals to more than 10 years in others. Eventually some individuals with frontotemporal dementia will need 24-hour care and monitoring at home or in an institutionalized care setting.

**Pierre Robin Syndrome**

Catel-Manzke syndrome is a rare association combining micrognathia, glossoptosis and cleft palate (Pierre Robin sequence) with an anomaly of both index fingers (accessory ossicle at the metacarpophalangeal joint with resulting ulnar deviation). It has been described in about 25 patients. Besides the main features, several associated malformations have also been described, mainly a cardiac defect and growth retardation. Less frequent findings included iris coloboma, hypertelorism, small palpebral fissures, low-set or posteriorly rotated ears, bilateral brachydactyly, bilateral fifth finger clinodactyly, pectus excavatum, dislocable knees, short halluces, and scoliosis. Cerebral ventriculomegaly was described in one case. Ten of the case reports centred largely on the development of affected children, two of whom had intellectual deficit: in one of these cases the deficit was mild, whereas in the other it was severe. Intellectual development was within normal limits for the other children studied. As the first described cases all involved boys, an X-linked recessive mode of inheritance was suggested for this syndrome. However, female cases (including a report of two sisters) were later described and only one case of male-to-male transmission has been reported. The proposed genetic etiology is a microdeletion, possibly resulting in a contiguous gene syndrome, but this can only be confirmed by continuing cytogenetic evaluation of additional cases with advanced techniques.

Pierre-Robin syndrome (or Pierre-Robin sequence) is characterised by triad of orofacial morphological anomalies consisting of retrognathism, glossoptosis and a posterior median velopalatal cleft. This condition is referred to as a sequence because the posterior cleft palate is a secondary defect associated with abnormal mandibular development: mandibular hypoplasia occurring early in gestation causes the tongue to be maintained high-up in the oral cavity, preventing fusion of the palatal shelves. The origin of the anomaly in mandibular development is variable but is rarely associated with an osseous defect. In most cases the mandibular malformation is a secondary defect resulting from antenatal orofacial hypomobility, usually related to a functional defect in the rhombencephalon (hind brain). This explains the frequency and severity of the manifestations in neonates, which include difficulties in coordinating suction, swallowing and respiration, early feeding difficulties, mis-swallowing, oesophageal motor anomalies, glossopharyngeal-laryngeal respiratory obstruction and vagal syncope. The prevalence of this syndrome has been estimated at 1 in 10 000 births, but precise values are difficult to obtain because the definition of the syndrome is variable, with some studies including cases were Pierre-Robin sequence occurs as part of a recognised syndrome. Isolated Pierre-Robin sequence (without any other associated malformation) occurs in about 50% of cases. Approximately 10% of these isolated forms are familial but the causative gene(s) has not yet been identified. If management of the clinical manifestations is successful during the first year of life, the prognosis is favourable. The glossoptosis, together with the feeding and respiratory problems, usually resolves during the first two years of life and growth of the mandible leads to correction of the retrognathism within three to six years. The cleft palate can be corrected by surgical intervention before the age of nine months. The neurological prognosis for these patients is also good. However, the persistent risk of otitis, transmission hypoacousia and phonation difficulties necessitate follow-up by an ear, nose and throat specialist and speech therapist. In one half of the cases, Pierre-Robin sequence occurs as part of a complex malformation syndrome. The nature of these anomalies is heterogeneous but they are most commonly collagenopathies, first arch anomalies, various chromosomal disorders (including Microdeletion 22q11), phenocopy syndromes associated with toxic agents (alcohol, sodium valproate) and other more complicated associations. The prognosis for patients with syndromic Pierre-Robin sequence varies depending on the syndrome involved. Pierre-Robin sequence is usually diagnosed at birth. Prenatal diagnosis is possible if the retrognathism is detected at ultrasound. An excess of amniotic fluid is a good diagnostic indicator. In contrast, the cleft palate is not directly visible but may be suspected if the position of the tongue is abnormal (posterior and high-up in the oral cavity). Genetic counselling should be offered to all families, even in the event of sporadic cases.

Pierre Robin Syndrome- faciodigital anomaly is characterised by the association of Pierre Robin sequence (retrognathia, cleft palate and glossoptosis) with facial dysmorphism (high forehead with frontal bossing) and digital anomalies (tapering fingers, hyperconvex nails, clinodactyly of the fifth fingers and short distal phalanges, finger-like thumbs and easily subluxated first metacarpophalangeal joints). It has been described in two half brothers born to the same mother. Growth and mental development were normal. Transmission appears to be X-linked recessive.

**Pityriasis Lichenoides**

Pityriasis lichenoides chronic is a chronic inflammatory skin condition possible caused by abnormal immune system functioning. It involves the development of a skin rash consisting of small skin bumps that change color, flatten and disappear over a matter of weeks.

The list of signs and symptoms mentioned in various sources for Pityriasis lichenoides chronica includes the 2 symptoms listed below:

Small pink skin bumps

Red-brown spots

**Polycystic Ovary Syndrome**

Polycystic ovarian syndrome (PCOS), also known by the name Stein-Leventhal syndrome, is a hormonal problem that causes women to have a variety of symptoms. It should be noted that most women with the condition have a number of small cysts in the ovaries. However, women may have cysts in the ovaries for a number of reasons, and it is the characteristic constellation of symptoms, rather than the presence of the cysts themselves, that is important in establishing the diagnosis of PCOS.

PCOS occurs in 5% to 10% of women and is the most common cause of infertility in women. The symptoms of PCOS may begin in adolescence with menstrual irregularities, or a woman may not know she has PCOS until later in life when symptoms and/or infertility occur. Women of all ethnicities may be affected.

The principal signs and symptoms of PCOS are related to menstrual disturbances and elevated levels of male hormones (androgens). Menstrual disturbances can include delay of normal menstruation (primary amenorrhea), the presence of fewer than normal menstrual periods (oligomenorrhea), or the absence of menstruation for more than three months (secondary amenorrhea). Menstrual cycles may not be associated with ovulation (anovulatory cycles) and may result in heavy bleeding.

Symptoms related to elevated androgen levels include acne, excess hair growth on the body (hirsutism), and male-pattern hair loss.

Other signs and symptoms of PCOS include:

obesity and weight gain,

elevated insulin levels and insulin resistance

oily skin,

dandruff,

infertility,

skin discolorations,

high cholesterol levels,

elevated blood pressure, and

multiple, small cysts in the ovaries.

Any of the above symptoms and signs may be absent in PCOS, with the exception of irregular or no menstrual periods. All women with PCOS will have irregular or no menstrual periods. Women who have PCOS do not regularly ovulate; that is, they do not release an egg every month. This is why they do not have regular periods and typically have difficulty conceiving.

No one is quite sure what causes PCOS, and it is likely to be the result of a number of both genetic (inherited) as well as environmental factors. Women with PCOS often have a mother or sister with the condition, and researchers are examining the role that genetics or gene mutations might play in its development. The ovaries of women with PCOS frequently contain a number of small cysts, hence the name poly=many cystic ovarian syndrome. A similar number of cysts may occur in women without PCOS. Therefore, the cysts themselves do not seem to be the cause of the problem.

A malfunction of the body's blood sugar control system (insulin system) is frequent in women with PCOS, who often have insulin resistance and elevated blood insulin levels, and researchers believe that these abnormalities may be related to the development of PCOS. It is also known that the ovaries of women with PCOS produce excess amounts of male hormones known as androgens. This excessive production of male hormones may be a result of or related to the abnormalities in insulin production.

Another hormonal abnormality in women with PCOS is excessive production of the hormone LH, which is involved in stimulating the ovaries to produce hormones and is released from the pituitary gland in the brain.

Other possible contributing factors in the development of PCOS may include a low level of chronic inflammation in the body and fetal exposure to male hormones.

Women with PCOS are at a higher risk for a number of illnesses, including high blood pressure, diabetes, heart disease, andcancer of the uterus (endometrial cancer).

Because of the menstrual and hormonal irregularities, infertility is common in women with PCOS. Because of the lack of ovulation, progesterone secretion in women with PCOS is diminished, leading to long-term unopposed estrogen stimulation of the uterine lining. This situation can lead to abnormal periods, breakthrough bleeding, or prolonged uterine bleeding in some women. Unopposed estrogen stimulation of the uterus is also a risk factor for the development of endometrial hyperplasia and cancer of the endometrium (uterine lining). However, medications can be given to induce regular periods and reduce the estrogenic stimulation of the endometrium (see below).

Obesity is associated with PCOS; about 60% of those diagnosed with PCOS in the U.S. are obese. Obesity not only compounds the problem of insulin resistance and type 2 diabetes (see below), but it also imparts cardiovascular risks. PCOS and obesity are associated with a higher risk of developing metabolic syndrome, a group of symptoms, including high blood pressure, that increase the chances of developing cardiovascular disease. It has also been shown that levels of C-reactive protein (CRP), a biochemical marker that can predict the risk of developing cardiovascular disease, are elevated in women with PCOS. Reducing the medical risks from PCOS-associated obesity is possible.

The risk of developing prediabetes and type 2 diabetes is increased in women with PCOS, particularly if they have a family history of diabetes. Obesity and insulin resistance, both associated with PCOS, are significant risk factor for the development of type 2 diabetes. Several studies have shown that women with PCOS have abnormal levels of LDL ("bad") cholesterol and lowered levels of HDL ("good") cholesterol in the blood. Elevated levels of blood triglycerides have also been described in women with PCOS.

Changes in skin pigmentation can also occur with PCOS. Acanthosis nigricans refers to the presence of velvety, brown to black pigmentation often seen on the neck, under the arms, or in the groin. This condition is associated with obesity and insulin resistance and occurs in some women with PCOS.

**Polyendocrinopathies, Autoimmune**

Polyendocrinopathies, Autoimmune are autoimmune diseases affecting multiple endocrine organs. Type I is characterized by childhood onset and chronic mucocutaneous candidiasis (cabdidiasis, chronic mucocutaneous), while type II exhibits any combination of adrenal insufficiency (Addison's disease), lymphocytic thyroiditis (thyroiditus, autoimmune;), hypoparathyroidism; and gonadal failure. In both types organ-specific antibodies against a variety of endocrine glands have been detected. The type II syndrome differs from type I in that it is associated with HLA- A1 and B8 haplotypes, onset is usually in adulthood, and candidiasis is not present.

**Prader-Willi Syndrome**

Prader-Willi syndrome is a complex genetic condition that affects many parts of the body. In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes mellitus (the most common form of diabetes).

People with Prader-Willi syndrome typically have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common, including temper tantrums, stubbornness, and compulsive behavior. Many affected individuals also have sleep abnormalities.

Additional features of this condition include distinctive facial features, short stature, and small hands and feet. Some people with Prader-Willi syndrome have unusually fair skin and light-colored hair. Both affected males and affected females have underdeveloped genitals. Puberty is delayed or incomplete, and most affected individuals are unable to have children (infertile).

Prader-Willi syndrome is caused by the loss of genes in a specific region of chromosome 15. People normally inherit one copy of this chromosome from each parent. Some genes are turned on (active) only on the copy that is inherited from a person's father (the paternal copy). This parent-specific gene activation is caused by a phenomenon called genomic imprinting. Prader-Willi syndrome occurs when the region of the paternal chromosome 15 containing these genes is missing.

Researchers are working to identify genes on chromosome 15 that are responsible for the characteristic features of Prader-Willi syndrome. They have determined that a deletion of the OCA2 gene on chromosome 15 is associated with unusually fair skin and light-colored hair in some affected individuals. The protein produced from this gene helps determine the coloring (pigmentation) of the skin, hair, and eyes. Researchers have not definitively connected any other genes with specific signs and symptoms of Prader-Willi syndrome.

Most cases of Prader-Willi syndrome (about 70 percent) occur when a segment of the paternal chromosome 15 is deleted in each cell. In another 25 percent of cases, a person with Prader-Willi syndrome has two copies of chromosome 15 inherited from his or her mother (maternal copies) instead of one copy from each parent. This phenomenon is called maternal uniparental disomy. Rarely, Prader-Willi syndrome can also be caused by a chromosomal rearrangement called a translocation, or by a mutation or other defect that abnormally turns off (inactivates) genes on the paternal chromosome 15. Each of these genetic changes results in a loss of gene function in a critical region of chromosome 15.

Most cases of Prader-Willi syndrome are not inherited, particularly those caused by a deletion in the paternal chromosome 15 or by maternal uniparental disomy. These genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development. Affected people typically have no history of the disorder in their family.

Rarely, a genetic change responsible for Prader-Willi syndrome can be inherited. For example, it is possible for a genetic defect that abnormally inactivates genes on the paternal chromosome 15 to be passed from one generation to the next.

**Pulmonary Fibrosis**

"Fibrosis" is a term used to refer to scarring, so pulmonary fibrosis means scarring throughout the lungs. Pulmonary fibrosis can be caused by many conditions including chronic inflammatory processes (sarcoidosis, Wegener's granulomatosis ), infections, environmental agents (asbestos, silica, exposure to certain gases), exposure to ionizing radiation (such as radiation therapy to treat tumors of the chest), chronic conditions (lupus, rheumatoid arthritis), and certain medications.

In a condition known as hypersensitivity pneumonitis, fibrosis of the lung can develop following a heightened immune reaction to inhaled organic dusts or occupational chemicals. This condition most often results from inhaling dust contaminated with bacterial, fungal, or animal products.

In some people, chronic pulmonary inflammation and fibrosis develop without an identifiable cause. Most of these people have a condition called idiopathic pulmonary fibrosis (IPF) that does not respond to medical therapy, while some of the other types of fibrosis, such as nonspecific interstitial pneumonitis (NSIP), may respond to immune suppressive therapy.

Synonyms (other names) for various types of pulmonary fibrosis that have been used in the past include chronic interstitial pneumonitis, Hamman-Rich syndrome, and diffuse fibrosing alveolitis.

Symptoms of pulmonary fibrosis include:

shortness of breath

coughing

diminished exercise tolerance.

Symptoms vary depending on the cause of the pulmonary fibrosis. The severity of symptoms and the progression (worsening) of symptoms over time can vary.

The most common cause, idiopathic pulmonary fibrosis, unfortunately often has slow and relentless progression. Early on, patients often complain of a dry unexplained cough. Often, slow and insidious onset of shortness of breath can set in. With time, dyspnea (shortness of breath) worsens. Primarily, dyspnea initially occurs only with activity and is often attributed to aging. With time, the dyspnea begins to occur with less and less activity. Eventually, the shortness of breath becomes disabling, limiting all activity and even occurring while sitting still. In rarer cases, the fibrosis can be rapidly progressive, with dyspnea and disability occurring in weeks to months of onset of the disease. This form of pulmonary fibrosis has been referred to as Hamman-Rich syndrome.

**Pupil Disorders**

Pupil Disorders are conditions which affect the structure or function of the pupil of the eye, including disorders of innervation to the pupillary constrictor or dilator muscles, and disorders of pupillary reflexes.

**Ramsay-Hunt syndrome**

Ramsay Hunt syndrome (also termed Hunt's Syndrome and herpes zoster oticus) is a herpes zoster virus infection of the geniculate ganglion of the facial nerve. It is caused by reactivation of herpes zoster virus that has previously caused chickenpox in the patient. Ramsay Hunt syndrome results in paralysis of the facial muscles on the same side of the face as the infection. So, the virus infects the facial nerve that normally innervates controls the muscles of the face. Ramsay Hunt syndrome is typically associated with a red rash and blisters (inflamed vesicles or tiny water-filled sacks in the skin) in or around the ear and eardrum and sometimes on the roof of the mouth or tongue.

The classic symptom that clinically distinguishes Ramsay Hunt syndrome is a red painful rash associated with blisters in the ears or mouth and facial paralysis (for example, eyelid or mouth) on one side of the face. Other symptoms such as ear pain, hearing loss, dizziness (or vertigo), dry eye, and changes in taste sensation may also occur.

Diagnosis of the syndrome is most often made by observing the symptoms described above (red painful rash with ear and or mouth blisters and one-sided facial paralysis). Also, a PCR test (polymerase chain reaction) can be performed on the fluid from the blisters to demonstrate the viral genetic material, but this test is not done routinely.

The syndrome is not contagious; however, the herpes zoster virus that can be found in the blisters of Ramsay Hunt syndrome can be transmitted to other people and cause chickenpox in those that are unvaccinated against chickenpox. Individuals with Ramsay Hunt syndrome should avoid contact with newborns, pregnant women, immunodepressed individuals, and people with no history of chickenpox, at least until all the blisters change to scabs.

Bell's palsy also is a result of injury to the facial nerve by virus infection, but the suspected cause of Bell's palsy (viral) has not been identified. Ramsey Hunt syndrome is caused by the Varicella virus (herpes zoster) that also causes chickenpox and shingles (a painful, blister-producing herpes zoster reinfection that usually occurs on one side of the body). There is no red rash associated with Bell's palsy as there is with Ramsey Hunt syndrome. Additionally, Ramsay Hunt syndrome is commonly more painful than Bell's palsy. However, both can cause eyelid and mouth paralysis on one side of the face.

Dyssynergia cerebellaris myoclona is a rare degenerative disease of the nerves characterized by epilepsy, muscle spasms, and gradually increasing tremors. Like Bell's palsy, this disease complex mimics many symptoms of Ramsay Hunt syndrome. Some investigators term the disease complex Ramsay Hunt syndrome type 2.

Treatment consists of antiviral agents (for example, acyclovir, valacyclovir or famciclovir) for about one week, steroids (prednisone), and pain medications. Best results are reported when treatment protocols are started within about three days after symptoms appear. Early treatment usually results in a better prognosis (see below). For children, the varicella vaccine can reduce the chance of getting chickenpox from which the syndrome comes (reactivation of the virus). However, once a person gets chickenpox, the person is susceptible to reactivation of the virus and thus can develop shingles and/or Ramsay Hunt syndrome. Fortunately, there is another vaccine, Zostavax, which is helpful in preventing viral reactivation. Consequently, shingles and Ramsay Hunt syndrome can be either prevented or their symptoms reduced if the vaccine is administered. Usually, this vaccine is given to individuals that have had chickenpox as children and are now age 60 or older. The CDC (U.S. Centers for Disease Control and Prevention) suggests the vaccine be routinely given to individuals aged 60 or older, as about 90% of the population has been exposed to chickenpox and about 20% of people that had chickenpox are likely to get shingles without the vaccine.

The prognosis for Ramsay Hunt syndrome is not as good as that for Bell's palsy. There is good clinical evidence to suggest that treatment with steroids, pain medications, and antiviral agents (like acyclovir, valacyclovir or famciclovir) improve recovery and lessen the extreme facial discomfort. pain. However, infrequent complications can develop, such as synkinesis (inappropriate nerve responses such as blinking or tear formation while trying to talk), eye damage, or rarely, viral spread to other nerves causing many other problems (for example, pain, confusion, weakness). Postherpetic neuralgia (pain due to nerve fiber damage by the virus) may also develop and persist for months to years.

**Raynaud Disease**

Disease, Raynaud is a condition resulting in skin discoloration of the fingers and/or toes when a person is exposed to changes in temperature (cold or hot) or to emotional events. This condition can occur alone or as a part of another disease (such as rheumatoid arthritis). When the condition occurs alone it is referred to as "Raynaud disease" or primary Raynaud phenomenon. When it accompanies other diseases (such as rheumatoid arthritis), it is called secondary Raynaud phenomenon.

The skin discoloration occurs because an abnormal spasm of the blood vessels causes a diminished blood supply. Initially, the digits involved turn white because of diminished blood supply, then turn blue because of prolonged lack of oxygen and finally, the blood vessels reopen, causing a local "flushing" phenomenon, which turns the digits red. This three-phase color sequence (white to blue to red), most often upon exposure to cold temperature, is characteristic of Raynaud disease.

The disease is named for the French physician Maurice Raynaud (1834-1881).

**Reiter Syndrome**

**Reiter syndrome:** A chronic form of inflammatory arthritis wherein the following three conditions are combined: (1) arthritis; (2) inflammation of the eyes (conjunctivitis); and (3) inflammation of the genital, urinary or gastrointestinal systems.

Reiter syndrome is a systemic rheumatic disease, meaning that it can and does affect organs as well as the joints. It can cause inflammation in many areas, including the eyes, mouth, lungs, kidneys, heart, and skin.

**Rett Syndrome**

Rett syndrome is an X-linked dominant neurological disorder that affects girls only and is one of the most common causes of mental retardation in females. Girls with the syndrome show normal development during the first 6-18 months of life followed first by a period of stagnation and then by rapid regression in motor and language skills. The hallmark of Rett syndrome is the loss of purposeful hand use and its replacement with stereotyped hand-wringing. Screaming fits and inconsolable crying are common.

Other key features include loss of speech, behavior reminiscent of autism, panic-like attacks, bruxism (grinding of teeth), rigid gait, tremors, intermittent hyperventilation, and microcephaly (small head). Seizures occur in about half of cases. The girls typically survive into adulthood, but are at risk of sudden unexplained death. Rett syndrome is due to mutation in the MECP2 gene (methyl-CpG-binding protein-2) on chromosome Xq28. The vast majority of cases are sporadic and result from a new mutation in the girl with Rett syndrome or inheritance of the mutation from a parent who has somatic or germline mosaicism with the MECP2 mutation in only some of their cells. Atypical Rett syndrome with MECP2 mutations has been found in patients previously diagnosed with autism, mild learning disability, and mental retardation with spasticity or tremor. Males with a MECP2 mutation suffer severe encephalopathy (brain disease) and die before their first birthday.

More detail: Rett syndrome is a uniform and striking, progressive neurologic developmental disorder and one of the most common causes of mental retardation in females.

After normal development up to the age of 6 to 18 months, developmental stagnation occurs followed by rapid deterioration of high brain functions. Within 1 to 2 years, this deterioration progresses to loss of speech, severe dementia, behavior reminiscent of autism, stereotypic hand-wringing movements, loss of purposeful use of the hands, jerky ataxia (wobbliness) of the trunk, intermittent hyperventilation, and microcephaly (small head).

Thereafter, a period of apparent stability lasts for decades. But additional neurologic abnormalities intervene insidiously These abnormalities include what is called spastic paraparesis (paralysis and spasticity of the legs) and epilepsy (seizures). A striking deceleration of growth has been found across all measurements in most girls with Rett syndrome who end up with short stature and microcephaly.

The mortality (death) rate among children with Rett syndrome is increased (1.2% per year). A high proportion (26%) of the deaths are sudden and associated with a heart conduction problem, namely an abnormally prolonged QT interval on the electrocardiogram.

Rett syndrome is a most unusual disease because ONLY GIRLS have it. It is an X-linked dominant disorder that is lethal in males. Females who receive the Rett syndrome gene (symbolized RTT) have Rett syndrome. Males who receive the RTT gene apparently die before birth. The RTT gene has been found on the X chromosome in chromosome band Xq28 near the very end of the long (q) arm of the X chromosome. Rett syndrome is caused by mutation in the gene encoding methyl-CpG-binding protein-2 (MECP2).

The syndrome that bears his name was first described by Andreas Rett, an Austrian pediatrician, in 1966. The frequency of Rett syndrome - about 1 in 10-20,000 girls - appears similar in southwest Sweden, North Dakota, and metropolitan Tokyo.

**Reye Syndrome**

Reye's syndrome facts

Reye's syndrome is a rare and severe illness affecting children.

Reye's syndrome is associated with viral infection and aspirin use.

Patients with Reye's syndrome present with vomiting and mental-status changes.

Diagnosing Reye's syndrome primarily depends on the clinical history of symptoms.

The most common abnormal laboratory tests with Reye's syndrome include elevated liver enzymes, elevated ammonia levels, and low serum glucose levels.

Treatment is supportive, and even with treatment severe cases result in permanent brain damage and death.

Since educating parents about the dangers of aspirin use, the incidence of Reye's syndrome has decreased markedly.

Reye's syndrome is a rare but often severe and even fatal illness that primarily occurs in children and adolescents. Children diagnosed with Reye's syndrome generally present with vomiting and mental-status changes. The illness can resolve spontaneously or progress to coma and death. Although the cause is still unclear, studies have identified that there is a relationship between some viral infections and the use of aspirin medications. The CDC recommended educating parents about the dangers of treating children with aspirin in the 1980s, and now the disease occurs very rarely. The syndrome was initially described in 1963 by Dr. Ralph Douglas Reye.

Although there has been extensive research into the cause of Reye's syndrome, it is still not completely understood. As mentioned above, the use of aspirin or aspirin-containing medications to treat children with some viral infections including chickenpox, influenza, and gastroenteritis has been shown to be associated with the development of the disease. Ultimately, the causes of symptoms associated with Reye's syndrome relate to dysfunction of the liver and a resultant increase in serum ammonia levels and other toxins. These toxins cause increased pressure in the brain and swelling, leading to brain dysfunction and can progress to death.

Most children diagnosed with Reye's syndrome have a history of a recent viral infection. Chickenpox and influenza are identified most often, though rotavirus (a cause of bowel inflammation or gastroenteritis) has also been described. In addition to the recent viral infection, most have a history of taking aspirin to control fever. Some researchers have suggested that children with undiagnosed metabolic disorders may also be at risk, though this is not completely clear.

The primary symptoms of Reye syndrome include uncontrolled vomiting and mental status changes. These symptoms are generally the result of increased intracranial pressure and brain swelling. If untreated and progressive, the disease is fatal. Even if identified and treated early, some patients will still have progressive disease resulting in death or permanent brain damage.

**Rubinstein-Taybi Syndrome**

Rubinstein-Taybi syndrome is characterized by congenital anomalies (microcephaly, specific facial characteristics, broad thumbs and halluces and postnatal growth retardation), intellectual deficit and behavioural characteristics. Birth prevalence is 1 in 100,000 to 125,000. Facial features, which become more prominent with age, include highly arched eyebrows, long eyelashes, downslanting palpebral fissures, beaked nose, highly arched palate and micrognathia. Talon cusps are very frequent on the permanent incisors. An unusual smile with almost complete closure of the eyes is present in most cases. Other physical findings may include eye anomalies (nasolacrimal duct obstruction, congenital glaucoma, and refractive errors), a variety of congenital heart defects, joint hypermobility, and skin anomalies (in particular keloid formation). Constipation is generally a life-long problem, and patients may become overweight during late childhood or early puberty. As children, patients have a marked ability to establish excellent social contacts. In adulthood, sudden mood changes and obsessive-compulsive behaviour become gradually more frequent. An increased risk of tumours (mainly leukaemia in childhood and meningeoma in adulthood) has been observed. The syndrome is almost always sporadic. Causes include: microdeletion of chromosome 16p13.3, CREB-binding protein mutations (_CBP_, 16p13.3) and E1A-binding protein mutations (_EP300_, 22q13). CBP and EP300 show a very high degree of homology and both play important roles as global transcriptional coactivators. The exact pathogenesis of the syndrome remains uncertain. The diagnosis is in essence based on clinical examination. A cytogenetic or molecular abnormality can be detected in about 55% of patients. The syndrome can sometimes be difficult to differentiate from Saethre-Chotzen syndrome and Cornelia de Lange syndrome (see these terms). The recurrence risk for parents of an index case is low (0.1%). There are no reports of affected children of siblings of an index case. The chance of patients having an affected child may be as high as 50%. If a cytogenetic or molecular abnormality was found in the affected child, reliable prenatal diagnosis is possible during future pregnancies through chorionic villus biopsy. Prenatal ultrasound only rarely allows a reliable diagnosis. Patient management is mainly symptomatic. Specialised educational programs are required, with early emphasis on psychomotor development and speech therapy. Life expectancy does not seem to be altered, except in children with complex cardiac defects. Malignancies and respiratory infections are the most common causes of death.

**Sandhoff Disease**

Sandhoff disease is a genetic disorder with symptoms that are very similar to those of Tay-Sachs disease (TSD) and that is characterized by accumulation of fatty material called GM2 ganglioside in the nerve cells of the brain. Symptoms begin around 6 months of age, with motor weakness, and progress to include difficulties with swallowing and breathing. Death usually occurs by age 3. Sandhoff disease is an autosomal recessive disorder caused by a mutation to chromosome 5. Unlike TSD, it is most common in the non-Jewish population.

**Sarcoma, Ewing's**

Sarcoma, Ewing is a malignant tumor that arises in a primitive nerve cell within bone or soft tissue and affects children and adolescents, especially between ages 10 and 20. Ewing sarcoma usually appears in the large bones of the arms and legs and the flat bones of the pelvis, spine, and ribs. Treatments include chemotherapy, surgery, and radiation therapy. The primitive nerve cell from which Ewing sarcoma arises also gives rise to a number of tumors, known as the Ewing family of tumors, which include Ewing sarcoma of bone, extraosseus (nonbone) Ewing sarcoma, primitive neuroectodermal tumor (PNET), and Askin tumor (PNET of the chest wall). Most Ewing family tumors have a translocation between chromosomes 11 and 22 that results in the fusion of the EWS gene on chromosome 22 with the transcription factor gene FLI1 on chromosome 11, leading to the production of a chimeric (fusion) protein. The remaining tumors in the Ewing family engage the EWS gene in other translocations that lead to formation of chimeric proteins. In all cases the chimeric protein is oncogenic; that is, it is responsible for the malignancy.

**Schwachman Diamond disease**

Shwachman-Diamond syndrome is marked by the association of an haematological defect with a dysmorphic syndrome characterised by lipomatosis of the pancreas resulting in external pancreatic insufficiency. This disease is very rare, with no more than a hundred cases reported in France. Other clinical signs include cutaneous effects (ichtyosis), bone defects (metaphyseal dysostosis, pectus carinatum), and psychomotor retardation. Magnetic resonance imaging (MRI) reveals a typical hyposignal in T2. Neutropaenia with deficient chemotaxis together with moderate thrombopaenia and anaemia and increased levels of foetal haemoglobulin have also been noted. This central haematological disturbance worsens and evolves towards aplasia in 25% of cases. Despite some similarities with Pearson syndrome, Shwachman-Diamond disease cannot be explained by mitochondrial DNA defects. Mutations occurring in the ubiquitous_SBDS_ gene, located on chromosome 7, are found in most patients. The functions of the causative gene are highly polymorphic, making it difficult to explain the complex clinical picture. As long as neutropaenia is moderate and asymptomatic, patient management should be nutritional (pancreatic enzyme, nutritional and vitamin support). Hematopoietic growth factor (granulocyte colony-stimulating factor, G-CSF) therapy is sometimes beneficial. Patients affected by this syndrome are at increased risk of secondary leukaemia (principally acute myeloblastic leukaemia type FAB 5 or 6) or a myelodysplastic syndrome with cytological abnormalities (in particular, clonal cytological abnormalities frequently affecting chromosome 7). In cases where the disease evolves towards medular aplasia or malignant transformation, bone marrow transplant is required.

**Shwartzman Phenomenon**

Shwartzman phenomenon is a body reaction to certain toxins which results in the formation of a blood clot which can causes affected tissue to die. The symptoms can vary depending on what part of the body is exposed to the endotoxin. The reaction may be localized or systemic.

The list of signs and symptoms mentioned in various sources for Shwartzman phenomenon includes the 3 symptoms listed below:

Necrosis

Hemorrhage

Ulceration

**Shy-Drager Syndrome**

Shy-Drager syndrome is a progressive disorder of the central and sympathetic nervous systems, also called multiple system atrophy with postural hypotension (an excessive drop in blood pressure when the patient stands up, causing dizziness or momentary blackouts). Symptoms of autonomic nervous system failure, such as constipation, impotence in men, and urinary incontinence, usually predominate early in the course of the disease. Later symptoms can include impaired speech, difficulties with breathing and swallowing, and inability to sweat (anhidrosis). Shy-Drager syndrome usually ends in death within 7 to 10 years of the diagnosis.

**Sjogren's Syndrome**

Sjögren's syndrome facts

Sjögren's syndrome is an autoimmune disease.

Sjögren's syndrome involves inflammation of glands and other tissues of the body.

About 90% of Sjögren's syndrome patients are female.

Sjögren's syndrome can be complicated by infections of the eyes, breathing passages, and mouth.

Sjögren's syndrome is typically associated with antibodies against a variety of body tissues (autoantibodies).

Diagnosis of Sjögren's syndrome can be aided by a saliva-gland biopsy.

Treatment of patients with Sjögren's syndrome is directed toward the particular areas of the body that are involved and complications, such as infection.

Sjögren's syndrome is an autoimmune disease characterized by dryness of the mouth and eyes. Autoimmune diseases feature the abnormal production of extra antibodies in the blood that are directed against various tissues of the body. The misdirected immune system in autoimmunity tends to lead to inflammation of tissues. This particular autoimmune illness features inflammation in glands of the body that are responsible for producing tears and saliva. Inflammation of the glands that produce tears (lacrimal glands) leads to decreased water production for tears and decreased saliva production and dry eyes. Inflammation of the glands that produce the saliva in the mouth (salivary glands, including the parotid glands) leads to dry mouth and dry lips.

Sjogren's syndrome with gland inflammation (resulting in dry eyes and mouth, etc.) that is not associated with another connective tissue disease is referred to as primary Sjögren's syndrome. Sjögren's syndrome that is also associated with a connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma, is referred to as secondary Sjögren's syndrome. Dryness of eyes and mouth, in patients with or without Sjögren's syndrome, is sometimes referred to as sicca syndrome.

While the exact cause of Sjögren's syndrome is not known, there is growing scientific support for genetic (inherited) factors. The genetic background of Sjögren's syndrome patients is an active area of research. The illness is sometimes found in other family members. It is also found more commonly in families that have members with other autoimmune illnesses, such as systemic lupus erythematosus, autoimmune thyroid disease, type Idiabetes, etc. About 90% of patients with Sjögren's syndrome are female.

Symptoms of Sjögren's syndrome can involve the glands, as above, but there are also possible effects of the illness involving other organs of the body (extraglandular manifestations).

When the tear gland (lacrimal gland) is inflamed from Sjögren's, the resulting eye dryness can progressively lead to eye irritation, decreased tear production, a "gritty" sensation, infection, and serious abrasion of the dome of the eye (cornea). Dry eyes can lead to infections of the eyes. The condition of having dry eyes is medically referred to as xerophthalmia.

Inflammation of the salivary glands can lead to mouth dryness, swallowing difficulties, dental decay, cavities, gum disease, mouth sores and swelling, and stones and/or infection of the parotid gland inside of the cheeks. Dry lips often accompany the mouth dryness. Dry mouth is medically referred to as xerostomia.

Other glands that can become inflamed, though less commonly, in Sjögren's syndrome include those of the lining of the breathing passages (leading to lung infections) and the vagina (sometimes causing pain during intercourse or recurrent vaginal infections).

Extraglandular (outside of the glands) problems in Sjögren's syndrome include fatigue, joint pain or inflammation (arthritis), Raynaud's phenomenon, lung inflammation, lymph node enlargement, and kidney, nerve, and muscle disease. A rare serious complication of Sjögren's syndrome is inflammation of the blood vessels (vasculitis), which can damage the tissues of the body that are supplied by these vessels.

A common disease that is occasionally associated with Sjögren's syndrome is autoimmune thyroiditis (Hashimoto's thyroiditis), which can lead to abnormal thyroid hormone levels detected by thyroid blood tests. Heartburn and difficulty swallowing can result from gastroesophageal reflux disease (GERD), another common condition associated with Sjögren's syndrome. A rare and serious disease that is uncommonly associated with Sjögren's syndrome is primary biliary cirrhosis, an autoimmune disease of the liver that leads to scarring of the liver tissue. A small percentage of patients with Sjögren's syndrome develop cancer of the lymph glands (lymphoma). This usually develops only after many years with the illness. Unusual lymph node swelling should be reported to the physician.

**Sjogren-Larsson Syndrome**

The Sjogren-Larsson syndrome is a genetic (inherited) disease usually characterized by a triad of clinical findings consisting of ichthyosis (thickened fish-like skin), spastic paraplegia (spasticity of the legs) and mental retardation.

The skin changes in the Sjogren-Larsson syndrome are similar to those in congenital ichthyosiform erythroderma, a genetic disease that results in fish-like, reddened skin. Hyperkeratosis (thickening of the skin) is a regular feature. Ecchymoses (bruises) are present at birth or soon after in the Sjogren-Larsson syndrome. Sweating is normal.

The spasticity can also affect the arms as well as the legs, resulting in spastic paraplegia. The mental retardation is significant. Most of the patients never walk. About half the patients have seizures.

Eye problems are also part of the syndrome. About half of cases have pigmentary degeneration of the retina. Glistening white dots on the retina are characteristic.

People with Sjogren-Larsson syndrome tend to be unusually short.

Sjogren in 1956 (and Sjogren and Larsson in 1957) suggested that all Swedes with the syndrome are descended from one ancestor in whom a mutation (a genetic change) occurred about 600 years ago. This mutation is now present in at least 1% of the population in northern Sweden. This phenomenon is called founder effect (because everyone is descended from one "founder" within what was once a tiny group of people).

The gene for the Sjogren-Larsson syndrome has been found situated on chromosome number 17 (in band 17p11.2). The presence in a person of one copy of the gene (the heterozygous state) is harmless. However, if two gene carriers (heterozygotes) mate, the risk for each of their children is one-quarter to receive both of their Sjorgren-Larsson genes and to have the syndrome. The inheritance of Sjogren-Larsson syndrome is thus termed autosomal (non-sexlinked) recessive.

The laboratory findings are critically important. There is a deficiency of an enzyme called fatty aldehyde dehydrogenase 10 (FALDH10)in the Sjogren-Larsson syndrome. The syndrome is due to a deficit of FALDH10 and the gene for the Sjogren-Larsson syndrome gene is synonymous with the FALDH10 gene.

Some clinical improvement has been reported to occur with fat restriction in the diet and supplementation with medium-chain triglycerides.

Persons of diverse and different ethnic origins are now known with the Sjogren-Larsson syndrome. They include not only Swedes but, for example, members of families of other European, Arabic, and native American (AmerIndian) descent. This is evidence for genetic homogeneity (what appears clinically to be one genetic disease is in reality due to a diversity of mutations. All of the mutations causing Sjogren-Larsson syndrome have proved to be changes in the FALDH gene.

The Sjogren-Larsson syndrome is sometimes called the T. Sjogren syndrome to distinguish it from the sicca syndrome, which was described by Henrick Sjogren, a Swedish ophthalmologist. The Sjogren of the Sjorgren-Larsson syndrome was Torsten Sjogren (1896-1974), professor of psychiatry at the celebrated Karolinska Hospital in Stockholm and a pioneer in modern psychiatry and medical genetics. Tage Larsson was similarly a Swedish physician.

The Sjogren-Larsson syndrome is also known as SLS; as the ichthyosis, spastic neurologic disorder, and oligophrenia (an old word for mental retardation) syndrome; as fatty alcohol: NAD+ oxidoreductase deficiency (FAO deficiency); as fatty aldehyde dehydrogenase deficiency (FALDH deficiency); or as fatty aldehyde dehydrogenase 10 deficiency (FALDH10 deficiency).

**Smith-Lemli-Opitz Syndrome**

Smith-Lemli-Opitz syndrome is a multiple congenital malformation syndrome caused by an abnormality in cholesterol metabolism, deficiency of the enzyme 7-dehydrocholesterol reductase (DHCR7), due to mutation of the DHCR7 gene on chromosome 11.

The syndrome is characterized by growth retardation, microcephaly (small head), mental retardation, and malformations that include distinctive facial features, cleft palate, heart defects, underdeveloped external genitalia in males, polydactyly (extra digits), and syndactyly (webbing) of the toes.

The syndrome is inherited in an autosomal recessive manner and, interestingly, is associated with low cholesterol levels in blood.

**Spinal Muscular Atrophies of Childhood**

Spinal muscular atrophy (SMA) is a genetic disease characterized by progressive degeneration of motor neurons in the spinal cord. The disorder causes weakness and wasting of the voluntary muscles. This weakness is often more severe in the legs than in the arms.

Most of the childhood SMAs are inherited in an autosomal recessive manner. Parents usually have no symptoms but carry one copy of an SMA gene. The risk for each of their children to receive two copies of the SMA gene (onefrom each parent) and to have SMA is one-quarter.

Genes for SMA have been identified and accurate diagnostic tests exist. There are many types of SMA. Some of the more common types are described below.

**SMA type I:** Also called Werdnig-Hoffmann disease, SMA type I is evident before birth - there may be a reduction in fetal movement during the final months of pregnancy - or within the first few months of life. Symptoms include floppiness of the limbs and trunk, feeble movements of the arms and legs, swallowing and feeding difficulties, and impaired breathing. Children with SMA type I never sit or stand and usually die before the age of 2.

**SMA type II:** The disease usually becomes apparent between 3 and 15 months of age. Children with SMA type II may have respiratory problems, floppy limbs, decreased or absent deep tendon reflexes (with no kneejerk reflex), and twitching of arm, leg, or tongue muscles. These children may learn to sit but will never be able to stand or walk. Life expectancy varies.

**SMA type III:** Also called Kugelberg-Welander disease, SMA type III appears between 2 and 17 years of age with an abnormal way of walking; difficulty running, climbing steps, or rising from a chair; and slight tremor of the fingers.

**Kennedy syndrome:** Also known as progressive spinobulbar muscular atrophy, Kennedy syndrome has its clinical onset between 15 and 60 years of age. It is inherited in an X-linked recessive manner. Women carry the gene on one of their two X chromosomes, but the disorder only occurs in their sons. The risk to each son of a carrier mother is one-half to receive the gene and manifest the disease. Features may include weakness of muscles in the tongue and face, difficulty swallowing, speech impairment, and excessive development of the mammary glands in males. The disorder is slowly progressive.

**Congenital SMA with Arthrogryposis**: This is a rare disorder characterized by persistent contracture of joints (arthrogryposis) evident at birth. Features include the severe contractures, curvature of the spine, chest deformity, respiratory problems, an unusually small jaw, and drooping upper eyelids.

**Adult SMA:** This disorder may begin between 40 and 60 years of age and progresses rapidly, with an average life expectancy of about 5 years from the onset of symptoms. Most cases prove to be variants of amyotrophic lateral sclerosis (ALS, commonly called Lou Gehrig's disease). Symptoms include progressive limb weakness and weakening of the muscles, difficulty speaking and swallowing, and respiratory problems.

**Is there any treatment for SMA?**

Treatment of all forms of SMA is symptomatic and supportive and includes treating pneumonia, curvature of the spine, and respiratory infections, if present. Also, physical therapy, orthotic supports, and rehabilitation are useful. Genetic counseling is imperative.

**What is the prognosis for SMA?**

The prognosis for individuals with SMA varies depending on the type of SMA and the degree of respiratory function. The patient's condition tends to deteriorate over time.

**What research is being done on SMA?**

Researchers have found specific genes that, when mutated, cause SMA. Several animal models of the disease have been developed as well as tests that can determine SMA gene function. This allows scientists to screen drugs that may be useful in treating SMA.

**Sturge-Weber Syndrome**

Sturge-Weber syndrome is a congenital, but not inherited, disorder that affects the skin, the neurological system, and sometimes the eyes and internal organs. The main sign of Sturge-Weber syndrome is a port wine stain birthmark. Neurological symptoms may include seizures and developmental delay. Also known as encephelotrigeminal angiomatosi.

**Sweating, Gustatory**

Sweating, gustatory is sweating on the forehead, face, scalp, and neck occurring soon after ingesting food. Some gustatory sweating is normal after eating hot, spicy foods. Otherwise, gustatory sweating is most commonly a result of damage to a nerve that goes to the parotid gland, the large salivary gland in the cheek. In this setting, referred to as Frey syndrome, the sweating is usually on one side of the head. Gustatory sweating is also a rare complication of diabetes mellitus. In this case sweating may occur on both sides of the head, with mild or substantial severity.

This distressing problem can be difficult to treat. Treatments used include oxybutynin chloride, propantheline bromide, and clonidine(brand name: Catapres). Recently, some success has been reported using topical applications of glycopyrrolate: the lotion was applied to the skin of the forehead and face, sparing the eyes and mouth.

**Sweet's Syndrome**

Sweet's syndrome (the eponym for acute febrile neutrophilic dermatosis) is characterized by a constellation of clinical symptoms, physical features, and pathologic findings which include fever, neutrophilia, tender erythematous skin lesions (papules, nodules, and plaques), and a diffuse infiltrate consisting predominantly of mature neutrophils that are typically located in the upper dermis. Several hundred cases of Sweet's syndrome have been published. Sweet's syndrome presents in three clinical settings: classical (or idiopathic), malignancy-associated, and drug-induced. Classical Sweet's syndrome (CSS) usually presents in women between the age of 30 and 50 years, it is often preceded by an upper respiratory tract infection and may be associated with inflammatory bowel disease and pregnancy. Approximately one-third of patients with CSS experience recurrence of the dermatosis. Malignancy-associated Sweet's syndrome (MASS) can occur as a paraneoplastic syndrome in patients with an established cancer or individuals whose Sweet's syndrome-related hematologic dyscrasia or solid tumor was previously undiscovered; MASS is most commonly related to acute myelogenous leukemia. The dermatosis can precede, follow, or appear concurrently with the diagnosis of the patient's cancer. Hence, MASS can be the cutaneous harbinger of either an undiagnosed visceral malignancy in a previously cancer-free individual or an unsuspected cancer recurrence in an oncology patient. Drug-induced Sweet's syndrome (DISS) most commonly occurs in patients who have been treated with granulocyte-colony stimulating factor, however, other medications may also be associated with DISS. The pathogenesis of Sweet's syndrome may be multifactorial and still remains to be definitively established. Clinical and laboratory evidence suggests that cytokines have an etiologic role. Systemic corticosteroids are the therapeutic gold standard for Sweet's syndrome. After initiation of treatment with systemic corticosteroids, there is a prompt response consisting of dramatic improvement of both the dermatosis-related symptoms and skin lesions. Topical application of high potency corticosteroids or intralesional corticosteroids may be efficacious for treating localized lesions. Other first-line oral systemic agents are potassium iodide and colchicine. Second-line oral systemic agents include indomethacin, clofazimine, cyclosporine, and dapsone. The symptoms and lesions of Sweet's syndrome may resolve spontaneously, without any therapeutic intervention; however, recurrence may follow either spontaneous remission or therapy-induced clinical resolution.

**Takayasu's Arteritis**

Takayasu disease is a chronic inflammatory disease of the aorta and its branch arteries. The cause is unknown. The disease is most common in young women of Asian descent and usually begins between 10 and 30 years of age. Symptoms include painful, cool, or blanched extremities, dizziness, headaches, chest and abdominal pain, and low-grade fever. The blood pressure is often high. The sedimentation rate (sed rate) may be elevated, reflecting inflammation. The diagnosis is confirmed by an angiogram of the arteries (arteriogram) showing abnormally narrowed and constricted arteries. The disease is treated with corticosteroids and immunosuppressive drugs when needed. Also known as Takayasu arteritis; Martorell syndrome; pulseless disease; and aortic arch syndrome.

**Tangier Disease**

A protein named ABC1 (ATP Binding Cassette 1) or CERP (Cholesterol Efflux Regulatory Protein) is able to orient cellular cholesterol towards the cell surface and to facilitate its transfer towards the core of HDL (see hypoalphalipopproteinemias). Tangier disease is recessively inherited, which means that both parental chromosomes should carry a mutation of the ABC1 gene. Disease onset is in childhood manifesting with corneal opacities and tonsil enlargement, which take a particular orange-yellow color, due to cholesterol deposition. Atherosclerosis and cholesterol accumulation within the rectal (end of the large intestine) mucosa are present. Liver and spleen are enlarged, neurologic symptoms are reported. The disseminated cholesterol accumulation in tissues contrasts with the absence of HDL and apo A1 in plasma. The identification of a mutation on the ABC1 gene identifies formally the cause of the disease. About one to two dozen cases of Tangier disease have been described worldwide.

**Tay-Sachs Disease**

Tay-Sachs disease is a genetic metabolic disorder caused by deficiency of the enzyme hexosaminidase A (hex-A) that results in a failure to process a lipid called GM2 ganglioside that accumulates in the brain and other tissues. Abbreviated TSD.

The classic form of TSD begins in infancy. The child usually develops normally for the first few months, but head control is lost by 6 to 8 months of age; the infant cannot roll over or sit up, spasticity and rigidity develop, and excessive drooling and convulsions become evident. Blindness and head enlargement occur by the second year. The disease worsens as the central nervous system progressively deteriorates. After age 2, constant nursing care is needed. Death generally occurs by age 5, due usually to cachexia (wasting away) or aspiration pneumonia. There are several forms of TSD. With juvenile TSD and adult TSD, the person has somewhat more hex-A and hence a later onset of clinical disease than with infantile TSD.

All known forms of TSD are inherited in autosomal recessive manner and are due to mutation of the gene for the alpha subunit of hex-A that is on chromosome 15q23-15q24. The frequency of TSD is relatively high in Ashkenazi Jews, particularly those whose ancestors came from Lithuania and Poland. This is believed due to founder effect, mutation in one of the founders of this group of people. Knowledge of the biochemical basis of TSD now permits screening for carrier status and prenatal diagnosis.

The disease is named for the English physician Waren Tay and New York neurologist Bernard (Barney) Sachs who made key early contributions to the rocognition of this disease. In 1881 Tay described an infant he had seen with progressive neurological impairment and the "cherry-red spots" in the retina characteristic of TSD. Sachs saw a child in 1887 and the child's sister in 1898 with the cherry-red spots and "arrested cerebral development" and in 1910 he demonstrated the presence of accumulated lipid in the brain and retina.

TSD was once called amaurotic familial idiocy (a term to avoid) and today it is also known as type 1 GM2-gangliosidosis, B variant GM2-gangliosidosis, hexosaminidase A deficiency, and hex-A deficiency.

**Thromboangiitis Obliterans**

Thromboangiitis obliterans or Buerger's disease is a segmental occlusive inflammatory condition of arteries and veins, with thrombosis and recanalization of the affected vessels. It is a nonatherosclerotic inflammatory disease affecting small and medium sized arteries and veins of upper and lower extremities. The disease is found worldwide, the prevalence among all patients with peripheral arterial disease ranges from values as low as 0.5 to 5.6% in Western Europe to values as high as 45 to 63% in India, 16 to 66% in Korea and Japan, and 80% among Ashkenazi Jews. The prevalence of the disease in the general population in Japan was estimated at 5/100,000 persons in 1985. The clinical criteria edited by Olin in 2000 include: age under 45 years; current or recent history of tobacco use; presence of distal-extremity ischemia, indicated by claudication, pain at rest, ischemic ulcers or gangrenes, and documented by non-invasive vascular testing; exclusion of autoimmune diseases, hypercoagulable states and diabetes mellitus; exclusion of a proximal source of emboli by echocardiography or arteriography; consistent arteriographic findings in the clinically involved and non-involved limbs. The etiology of thromboangiitis obliterans is unknown, but use or exposure to tobacco is central to the initiation and progression of the disease. If the patient smokes, stopping completely is an essential first step of treatment. The role of other treatments including vasodilating or anti-clotting drugs, surgical revascularization or sympathectomy in preventing amputation or treating pain, remains unclear.

**Tietze's Syndrome**

Tietze's syndrome is the inflammation and swelling of the cartilage that joins the ribs to the breast bone.

The list of signs and symptoms mentioned in various sources for Tietze's syndrome includes the 3 symptoms listed below:

Chest pain

Chest tenderness

Rib swelling

Causes of Broader Categories of Tietze's syndrome: Review the causal information about the various more general categories of medical conditions:

Rib conditions

Chest conditions

Cartilage conditions

Musculoskeletal conditions

Non-pathogenic inflammatory conditions

**Togaviridae Infections**

Togaviridae disease is the infection with any of a number of togaviridae viruses which can cause conditions such as Equine encephalitis, Ross River virus and Rubella virus. Symptoms are determined by the type of virus involved. Togaviridae are arboviruses and are transmitted by arthropods.

The list of signs and symptoms mentioned in various sources for Togaviridae disease includes the 17 symptoms listed below:

Asymptomatic

Febrile illness

Fever

Headache

Vomiting

Drowsiness

Irritability

Nausea

Confusion

Weakness

Stiff neck

Seizures

Chills

Arthritic pain

Rash

Hemorrhagic fever

Flu-like symptoms

The primary cause of Togaviridae disease is the result of transmission of an infectious disease. Some subtypes of this disease are contagious - spread easily between people, while other subtypes are infectious - transmitted by a pathogenic organism.

**Tolosa-Hunt Syndrome**

Tolosa-Hunt syndrome is an ophthalmoplegic syndrome, affecting all age groups, characterized by acute attacks (lasting a few days to a few weeks) of periorbital pain, ipsilateral ocular motor nerve palsies, ptosis, disordered eye movements and blurred vision usually caused by a non-specific inflammatory process in the cavernous sinus and superior orbital fissure. It has an unpredicatable course with spontaneous remission occurring in some and recurrence of attacks in others.

**Tourette Syndrome**

Tourette syndrome (TS) is a neurological disorder characterized by repetitive, stereotyped, involuntary movements and vocalizations called tics. The disorder is named for Dr. Georges Gilles de la Tourette, the pioneering French neurologist who in 1885 first described the condition in an 86-year-old French noblewoman. The early symptoms of Tourette syndrome are almost always noticed first in childhood, with the average onset between the ages of 7 and 10 years. Tourette syndrome occurs in people from all ethnic groups; males are affected about three to four times more often than females. It is estimated that 200,000 Americans have the most severe form of Tourette syndrome, and as many as one in 100 exhibit milder and less complex symptoms such as chronic motor or vocal tics or transient tics of childhood. Although Tourette syndrome can be a chronic condition with symptoms lasting a lifetime, most people with the condition experience their worst symptoms in their early teens, with improvement occurring in the late teens and continuing into adulthood.

Tics are classified as either simple or complex.

**Simple tics**

Simple motor tics are sudden, brief, repetitive movements that involve a limited number of muscle groups. Some of the more common simple tics include eye blinking and other vision irregularities, facial grimacing, shoulder shrugging, and head or shoulder jerking. Simple vocalizations might include repetitive throat-clearing, sniffing, or grunting sounds.

**Complex tics**

Complex tics are distinct, coordinated patterns of movements involving several muscle groups. Complex motor tics might include facial grimacing combined with a head twist and a shoulder shrug. Other complex motor tics may actually appear purposeful, including sniffing or touching objects, hopping, jumping, bending, or twisting. Simple vocal tics may include throat-clearing, sniffing/snorting, grunting, or barking. More complex vocal tics include words or phrases. Perhaps the most dramatic and disabling tics include motor movements that result in self-harm such as punching oneself in the face or vocal tics including coprolalia (uttering swear words) or echolalia (repeating the words or phrases of others). Some tics are preceded by an urge or sensation in the affected muscle group, commonly called a premonitory urge.

Some with Tourette syndrome will describe a need to complete a tic in a certain way or a certain number of times in order to relieve the urge or decrease the sensation. Tics are often worse with excitement or anxiety and better during calm, focused activities. Certain physical experiences can trigger or worsen tics, for example tight collars may trigger neck tics, or hearing another person sniff or throat-clear may trigger similar sounds. Tics do not go away during sleep but are often significantly diminished.

Tics come and go over time, varying in type, frequency, location, and severity. The first symptoms usually occur in the head and neck area and may progress to include muscles of the trunk and extremities. Motor tics generally precede the development of vocal tics and simple tics often precede complex tics. Most patients experience peak tic severity before the mid-teen years with improvement for the majority of patients in the late teen years and early adulthood. Approximately 10 percent of those affected have a progressive or disabling course that lasts into adulthood.

Although the symptoms of Tourette syndrome are involuntary, some people can sometimes suppress, camouflage, or otherwise manage their tics in an effort to minimize their impact on functioning. However, people with Tourette syndrome often report a substantial buildup in tension when suppressing their tics to the point where they feel that the tic must be expressed. Tics in response to an environmental trigger can appear to be voluntary or purposeful but are not.

Although the cause of Tourette syndrome is unknown, current research points to abnormalities in certain brain regions (including the basal ganglia, frontal lobes, and cortex), the circuits that interconnect these regions, and the neurotransmitters (dopamine, serotonin, and norepinephrine) responsible for communication among nerve cells. Given the often complex presentation of Tourette syndrome, the cause of the disorder is likely to be equally complex.

Many with Tourette syndrome experience additional neurobehavioral problems including inattention; hyperactivity and impulsivity (attention deficit hyperactivity disorder-ADHD) and related problems with reading, writing, and arithmetic; and obsessive-compulsive symptoms such as intrusive thoughts/worries and repetitive behaviors. For example, worries about dirt and germs may be associated with repetitive hand-washing, and concerns about bad things happening may be associated with ritualistic behaviors such as counting, repeating, or ordering and arranging. People with Tourette syndrome have also reported problems with depression or anxiety disorders, as well as other difficulties with living, that may or may not be directly related to Tourette syndrome. Given the range of potential complications, people with Tourette syndrome are best served by receiving medical care that provides a comprehensive treatment plan.

Tourette syndrome is a diagnosis that doctors make after verifying that the patient has had both motor and vocal tics for at least 1 year. The existence of other neurological or psychiatric conditions [these include childhood-onset involuntary movement disorders such as dystonia, or psychiatric disorders characterized by repetitive behaviors/movements (for example, stereotypic behaviors in autism and compulsive behaviors in obsessive-compulsive disorder - OCD] can also help doctors arrive at a diagnosis. Common tics are not often misdiagnosed by knowledgeable clinicians. But atypical symptoms or atypical presentation (for example, onset of symptoms in adulthood) may require specific specialty expertise for diagnosis. There are no blood or laboratory tests needed for diagnosis, but neuroimaging studies, such as magnetic resonance imaging (MRI), computerized tomography (CT), and electroencephalogram (EEG) scans, or certain blood tests may be used to rule out other conditions that might be confused with Tourette syndrome. It is not uncommon for patients to obtain a formal diagnosis of Tourette syndrome only after symptoms have been present for some time. The reasons for this are many. For families and physicians unfamiliar with Tourette syndrome, mild and even moderate tic symptoms may be considered inconsequential, part of a developmental phase, or the result of another condition. For example, parents may think that eye blinking is related to vision problems or that sniffing is related to seasonal allergies. Many patients are self-diagnosed after they, their parents, other relatives, or friends read or hear about Tourette syndrome from others.

Because tic symptoms do not often cause impairment, the majority of people with Tourette syndrome require no medication for tic suppression. However, effective medications are available for those whose symptoms interfere with functioning. Neuroleptics are the most consistently useful medications for tic suppression; a number are available but some are more effective than others (for example, haloperidol and pimozide).

Unfortunately, there is no one medication that is helpful to all people with Tourette syndrome, nor does any medication completely eliminate symptoms. In addition, all medications have side effects. Most neuroleptic side effects can be managed by initiating treatment slowly and reducing the dose when side effects occur. The most common side effects of neuroleptics include sedation, weight gain, and cognitive dulling. Neurological side effects such as tremor, dystonic reactions (twisting movements or postures), parkinsonian-like symptoms, and other dyskinetic (involuntary) movements are less common and are readily managed with dose reduction.

Discontinuing neuroleptics after long-term use must be done slowly to avoid rebound increases in tics and withdrawal dyskinesias. One form of withdrawal dyskinesia called tardive dyskinesia is a movement disorder distinct from Tourette syndrome that may result from the chronic use of neuroleptics. The risk of this side effect can be reduced by using lower doses of neuroleptics for shorter periods of time. Other medications may also be useful for reducing tic severity, but most have not been as extensively studied or shown to be as consistently useful as neuroleptics. Additional medications with demonstrated efficacy include alpha-adrenergic agonists such as clonidine and guanfacine. These medications are used primarily for hypertension but are also used in the treatment of tics. The most common side effect from these medications that precludes their use is sedation. Effective medications are also available to treat some of the associated neurobehavioral disorders that can occur in patients with Tourette syndrome. Recent research shows that stimulant medications such as methylphenidate and dextroamphetamine can lessen ADHD symptoms in people with Tourette syndrome without causing tics to become more severe. However, the product labeling for stimulants currently contraindicates the use of these drugs in children with tics/Tourette syndrome and those with a family history of tics. Scientists hope that future studies will include a thorough discussion of the risks and benefits of stimulants in those with Tourette syndrome or a family history of Tourette syndrome and will clarify this issue. For obsessive-compulsive symptoms that significantly disrupt daily functioning, the serotonin reuptake inhibitors (clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline) have been proven effective in some patients. Psychotherapy may also be helpful. Although psychological problems do not cause Tourette syndrome, such problems may result from Tourette syndrome. Psychotherapy can help the person with Tourette syndrome better cope with the disorder and deal with the secondary social and emotional problems that sometimes occur. More recently, specific behavioral treatments that include awareness training and competing response training, such as voluntarily moving in response to a premonitory urge, have shown effectiveness in small controlled trials. Larger and more definitive NIH-funded studies are underway.

Evidence from twin and family studies suggests that Tourette syndrome is an inherited disorder. Although early family studies suggested an autosomal dominant mode of inheritance (an autosomal dominant disorder is one in which only one copy of the defective gene, inherited from one parent, is necessary to produce the disorder), more recent studies suggest that the pattern of inheritance is much more complex. Although there may be a few genes with substantial effects, it is also possible that many genes with smaller effects and environmental factors may play a role in the development of Tourette syndrome. Genetic studies also suggest that some forms of ADHD and OCD are genetically related to Tourette syndrome, but there is less evidence for a genetic relationship between Tourette syndrome and other neurobehavioral problems that commonly co-occur with Tourette syndrome. It is important for families to understand that genetic predisposition may not necessarily result in full-blown Tourette syndrome; instead, it may express itself as a milder tic disorder or as obsessive-compulsive behaviors. It is also possible that the gene-carrying offspring will not develop any Tourette syndrome symptoms. The sex of the person also plays an important role in Tourette syndrome gene expression. At-risk males are more likely to have tics and at-risk females are more likely to have obsessive-compulsive symptoms. People with Tourette syndrome may have genetic risks for other neurobehavioral disorders such as depression or substance abuse. Genetic counseling of individuals with Tourette syndrome should include a full review of all potentially hereditary conditions in the family.

Although there is no cure for Tourette syndrome, the condition in many individuals improves in the late teens and early 20s. As a result, some may actually become symptom-free or no longer need medication for tic suppression. Although the disorder is generally lifelong and chronic, it is not a degenerative condition. Individuals with Tourette syndrome have a normal life expectancy. Tourette syndrome does not impair intelligence. Although tic symptoms tend to decrease with age, it is possible that neurobehavioral disorders such as depression, panic attacks, mood swings, and antisocial behaviors can persist and cause impairment in adult life.

Although students with Tourette syndrome often function well in the regular classroom, ADHD, learning disabilities, obsessive-compulsive symptoms, and frequent tics can greatly interfere with academic performance or social adjustment. After a comprehensive assessment, students should be placed in an educational setting that meets their individual needs. Students may require tutoring, smaller or special classes, and in some cases special schools. All students with Tourette syndrome need a tolerant and compassionate setting that both encourages them to work to their full potential and is flexible enough to accommodate their special needs. This setting may include a private study area, exams outside the regular classroom, or even oral exams when the child's symptoms interfere with his or her ability to write. Untimed testing reduces stress for students with Tourette syndrome.

**Uveomeningoencephalitic Syndrome**

Uveomeningoencephalitic syndrome is a syndrome characterized by bilateral granulomatous uveitis with iritis and secondary glaucoma, premature alopecia, symmetrical vitiligo, poliosis circumscripta (a strand of depigmented hair), hearing disorders, and meningeal signs (neck stiffness and headache). Examination of the cerebrospinal fluid reveals a pattern consistent with meningitis, aseptic

These medical condition or symptom topics may be relevant to medical information for Uveomeningoencephalitic syndrome:

Granulomatous

Granulomatous disease

UVEITIS (59 causes)

IRITIS (60 causes)

GLAUCOMA (150 causes)

Premature

ALOPECIA

VITILIGO (10 causes)

Poliosis

Strand

.

**Waardenburg's Syndrome**

Waardenburg syndrome is a genetic disorder that causes deafness, white forelock (a frontal white blaze of hair), a difference of color between the iris of one eye and the other (heterochromia iridis), white eye lashes, and wide-set inner corners of the eyes.

The deafness is typically congenital (present at birth), bilateral, profound sensorineural (nerve) deafness. The severity of Waardenburg syndrome (WS) varies and about 40 percent of affected persons escape the deafness. The white forelock may be present at birth. The majority of individuals with WS have the white forelock or early graying of the scalp hair before age 30.

WS is inherited in an autosomal dominant manner in which the heterozygous state (with one copy of the gene) is sufficient to cause the syndrome. The homozygous form of WS with two copies of the gene is a very severe (and fortunately rare) disorder with very severe upper-limb defects that has been called the Klein-Waardenburg syndrome.

The gene for classic WS, symbolized WS1, is on chromosome 2 (in band q35) and is the PAX3 gene which encodes a DNA-binding transcription factor that is expressed in the early embryo. The syndrome is named for a Dutch eye doctor named Petrus Johannes Waardenburg (1886-1979) who first noticed that people with differently colored eyes often had a hearing impairment.

**Waldenstrom Macroglobulinemia**

Waldenstrom macroglobulinemia is a chronic low-grade (indolent) type of lymphoma due to a malignant clone of plasma cells. These plasma cells multiply out of control, invade the bone marrow, lymph nodes, and spleen, and characteristically produce huge amounts of a large-sized antibody called macroglobulin or IgM. The excess IgM causes the blood to be hyperviscous (to thicken).

Waldenstrom macroglobulinemia can occur in younger people but is usually seen in people over age 65. The disease is more common among men than women and among whites than blacks.

Signs and symptoms of the disease may include enlarged lymph nodes or spleen (splenomegaly), fatigue, headaches, weight loss, a tendency to bleed easily, visual problems, confusion, dizziness, and loss of coordination. The symptoms are largely due to the thickening of the blood. In extreme cases, the increased concentration of IgM in the blood can lead to heart failure.

The treatment depends upon the viscosity of the patient's blood. Patients with pronounced hyperviscosity usually receive chemotherapy (anticancer drugs). A type of treatment called plasmapheresis may be performed to relieve symptoms such as excessive bleeding and dizziness. In this procedure, the blood plasma (which contains the antibody IgM) is removed from the patient. Other parts of the blood (red blood cells, white blood cells, and platelets) are returned to the patient along with a plasma substitute. Interferon alpha, a form of biological therapy, may also help relieve symptoms.

**Wegener Granulomatosis**

Wegener's granulomatosis is a uncommon type of inflammation of small arteries and veins (vasculitis). It classically involves inflammation of the arteries that supply blood to the tissues of the lungs, the nasal passages (sinuses), and the kidneys. "Incomplete" forms exist that only involve one of these areas. When both lungs and kidneys are affected, the condition is sometimes referred to as generalized Wegener's granulomatosis. When only the lungs are involved, the condition is sometimes referred to as limited Wegener's granulomatosis.

Wegener's granulomatosis usually affects young or middle-aged adults. Although it is uncommon in children, it can affect people at any age. The cause of Wegener's granulomatosis is not known.

Symptoms of Wegener's granulomatosis include fatigue, weight loss, fevers, shortness of breath, bloody sputum, joint pains, and sinus inflammation (sinusitis). Nasal ulcerations and even bloody nasal discharge can occur. Other areas of the body that can also become inflamed in patients with Wegener's granulomatosis include the eyes, the nerves (neuropathy), the middle ear (otitis media), and the skin resulting in skin nodules or ulcers.

Abnormal lab findings in patients with Wegener's granulomatosis include urine tests that detect protein and red blood cells in the urine (not visible to the naked eye) and x-ray tests of the chest and sinuses which detect abnormalities resulting from lung and sinus inflammation. Blood tests that detect the abnormal inflammation include the sedimentation rate (sed rate) and C-reactive protein. A more specific blood test used to diagnose and monitor Wegener's granulomatosis is the antineutrophil cytoplasmic antibody (ANCA test), which is commonly elevated when the disease is active.

The diagnosis of Wegener's granulomatosis is confirmed by detecting both abnormal cellular formations, called granulomas, and vasculitis in a biopsy of tissue involved with the inflammatory process. For examples, an open lung biopsy or a kidney biopsy are commonly used in making a diagnosis of Wegener's granulomatosis.

Wegener's granulomatosis is a serious disease and without treatment can be fatal within months. Treatment is directed toward stopping the inflammation process by suppressing the immune system.

Medications used to treat Wegener's granulomatosis include high-dose cortisone (prednisone) and the immunosuppressive drug cyclophosphamide (Cytoxan). Recent reports also suggest that trimethoprim/sulfamethoxazole (Bactrim) can also be helpful to prevent relapse of disease activity in patients with Wegener's granulomatosis.

Cytoxan that is taken by mouth with prednisone until the disease is in remission and then switched to methotrexate for two years and tapered off has been reported to be effective and less toxic than the traditional long-term Cytoxan treatment.

Methotrexate has recently been introduced as a drug for Cytoxan treatment failures. Moreover, it now appears that Cytoxan will not be necessary in order to maintain long-term remission and that doctors can convert to the less toxic methotrexate for maintenance. The reports also demonstrate that methotrexate can eventually be tapered off entirely after two years. Azathioprine (Imuran) has also been used as a maintenance medication after Cytoxan. Recently, intravenous immunoglobulin therapy (IVIG) has been shown to be helpful in treating relapses of Wegener's granulomatosis. Also, preliminary studies suggest that rituximab (Rituxan) may be helpful to maintain remission once the initial inflammatory disease has been controlled using medications mentioned above. These new regimens are welcome news for patients with Wegener's granulomatosis as medical researchers are searching for better treatments.

Wegener's Granulomatosis At A Glance

Wegener's granulomatosis is an uncommon disease that involves inflammation of blood vessels (vasculitis).

Symptoms of Wegener's granulomatosis include fatigue, weight loss, fevers, shortness of breath, bloody sputum, joint pains, and sinus inflammation.

Diagnosis of Wegener's granulomatosis is confirmed by detecting both abnormal cellular formations, called granulomas, and vasculitis.

Treatment is directed toward stopping the inflammation process by suppressing the immune system.

**Weil Disease**

Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia marked by disproportionate short stature and the characteristic Madelung wrist deformity (see this term).

Prevalence of LWD is unknown.

Short stature is present from birth with mesomelic shortening of the limbs (shortening of the middle segments of the forearms and lower legs). Madelung deformity may only be detected in puberty. The wrist deformity is bilateral and is characterized by shortened and bowed radii and ulnae leading to dorsal dislocation of the distal ulna and limited mobility of the wrist and elbow. Expression is variable but the clinical features are generally more severe in females. Male patients show an athletic body habitus due to muscular hypertrophy, without any underlying muscle disorder. Intelligence is normal.

In around 70 % of cases, LWD is caused by haploinsufficiency of the short stature homeobox (_SHOX_) gene, which maps to the pseudoautosomal region 1 (PAR1) of the sexual chromosomes (Xp22.33 and Yp11.32). Haploinsufficiency results from heterozygous mutations and deletions of _SHOX_, or of the downstream PAR1 (where _SHOX_ enhancer elements are located). The molecular defect remains unknown in the remaining 30% of LWD cases. _SHOX_-associated LWD is part of a spectrum of disorders (ranging from the most severe Langer mesomelic dysplasia (LMD) to LWD, isolated Madelung deformity and so-called idiopathic short stature; see these terms), all associated with _SHOX_/PAR1 anomalies. The prevalence of_SHOX_/PAR1 mutations is estimated at 1/1000.

Diagnosis of LWD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (microsatellite marker analysis, FISH or, preferably, MLPA for PAR1 deletions, HRM, dHPLC and/or DNA sequencing for point mutations, small deletions and insertions of _SHOX_).

Differential diagnoses should include the other SHOX-related haploinsufficiency disorders and related conditions such as Turner syndrome and distal monosomy Xp (see these terms).

Prenatal testing is available but not common.

LWD is inherited in a pseudoautosomal dominant manner with each child of an affected individual having a 50% chance of inheriting the mutation. If both parents have LWD, the offspring will have a 50% chance of having LWD, a 25% chance of having LMD, and a 25% chance of having neither condition.

Management should include regular surveillance with biannual height evaluations and annual wrist radiographs. Treatment options include administration of recombinant human GH (rhGH) to improve final adult height; or concurrent use of rhGH and gonadotrophin-releasing hormone agonist (GnRHa) to prevent the blunted pubertal growth spurt caused by the presence of estrogen. Molecular genetic testing of at-risk family members ensures early treatment with rhGH therapy to improve growth. Wrist splints, supports and ergonomic devices may reduce wrist discomfort. In some cases, surgical intervention (physiolysis of the ulnar aspect of the distal radius and excision of the Vickers ligament) is required in mid-to-late childhood and may decrease pain and restore wrist function.

Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of the lens, severe myopia, and glaucoma. The prevalence is not documented. Short stature (usually below the third percentile) and brachydactyly are present in 98% of patients. The following frequencies of ophthalmological manifestations are observed: myopia 94%, microspherophakia 84%, ectopia lentis 73%, glaucoma 80%, and cataract 23%. Other features include joint limitations, muscular build, thickened skin, and cardiac abnormalities (pulmonary valve stenosis, mitral valve insufficiency, aortic valve stenosis, ductus arteriosus, and ventricular septal defect). Intellectual deficit has been reported in 13% of cases and is always mild. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described. The AR mode of inheritance appears to be more frequent and homozygous mutations within the _ADAMST10_ gene (19p13.3-p13.2) have been found. _ADAMTS10_ is a member of the extracellular matrix protease family and is expressed in skin, fetal chondrocytes, and fetal and adult hearts. Electron microscopy and immunological studies of skin fibroblasts from WMS patients suggest that the syndrome is associated with impairment of the extracellular matrix. Heterozygous mutations within the _FBN1_ gene (15q21.1) have been identified in patients and are transmitted in an AD manner, giving another example of the large clinical expressivity of fibrillin-1. Clinical homogeneity has been demonstrated despite the genetic heterogeneity in AR and AD families. However, this leads to difficulties in genetic counseling of sporadic cases. Some heterozygotes for AR WMS present with some mild clinical manifestations of the disease, such as brachydactyly. Prenatal diagnosis has never been reported. Prognosis is good. Patients should be followed for ophthalmologic complications in particular, and physiotherapy can be proposed for joint stiffness.

**Weissenbacher-Zweymuller syndrome**

Weissenbacher-Zweymuller syndrome (WZS) is characterized by short stature at birth, neonatal micrognathia, cleft palate, rhizomelic chondrodysplasia with 'dumbbell' shaped arm and leg bones, hypertelorism and vertebral coronal clefts. WZS is a very rare condition, only a few families have been reported worldwide. WZS patients have a period of gradual growth that leads to normal physical development by age 5 to 6 years and final moderate short stature rather than normal stature. Hearing loss is common. Absence of ocular abnormalities differentiates WZS from Stickler syndrome. WZS is caused by heterozygous mutations in the _COL11A2_ gene and transmitted as an autosomal dominant trait.

**Williams Syndrome**

Definition: A genetic disorder characterized by mild mental retardation, unique personality characteristics, unusual facial features, and cardiovascular disease. The level of calcium tends to be high in blood (hypercalcemia) and urine (hypercalciuria).

Mental retardation is the rule and ranges from severe to mild. Personality features include overfriendliness, general anxiety, and attention deficit disorder. Facial features include narrow forehead, fullness about the eyes, short nose, flat midface, full lips, wide mouth, small jaw, and prominent earlobes. Supravalvar aortic stenosis (narrowing of the aorta just above the valve) is the most common and important cardiovascular abnormality.

Williams syndrome is inherited in an autosomal dominant manner and is due to a small chromosome deletion. Most cases are new occurrences but parent-to-child transmission is known. The region deleted is from chromosome 7 (band 7q11) and includes the ELN (elastic) gene, a useful molecular marker in tests to detect the deletion. The syndrome is due not merely to the loss of ELN but to contiguous gene deletion, loss of a series of adjacent genes.

Williams syndrome is a developmental disorder that affects many parts of the body. This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems.

People with Williams syndrome typically have difficulty with visual-spatial tasks such as drawing and assembling puzzles, but they tend to do well on tasks that involve spoken language, music, and learning by repetition (rote memorization). Affected individuals have outgoing, engaging personalities and tend to take an extreme interest in other people. Attention deficit disorder (ADD), problems with anxiety, and phobias are common among people with this disorder.

Young children with Williams syndrome have distinctive facial features including a broad forehead, a short nose with a broad tip, full cheeks, and a wide mouth with full lips. Many affected people have dental problems such as small, widely spaced teeth and teeth that are crooked or missing. In older children and adults, the face appears longer and more gaunt.

A form of cardiovascular disease called supravalvular aortic stenosis (SVAS) occurs frequently in people with Williams syndrome. Supravalvular aortic stenosis is a narrowing of the large blood vessel that carries blood from the heart to the rest of the body (the aorta). If this condition is not treated, the aortic narrowing can lead to shortness of breath, chest pain, and heart failure. Other problems with the heart and blood vessels, including high blood pressure (hypertension), have also been reported in people with Williams syndrome.

Additional signs and symptoms of Williams syndrome include abnormalities of connective tissue (tissue that supports the body's joints and organs) such as joint problems and soft, loose skin. Affected people may also have increased calcium levels in the blood (hypercalcemia) in infancy, developmental delays, problems with coordination, and short stature. Medical problems involving the eyes and vision, the digestive tract, and the urinary system are also possible.

Williams syndrome affects an estimated 1 in 7,500 to 20,000 people.

Williams syndrome is caused by the deletion of genetic material from a specific region of chromosome 7. The deleted region includes more than 25 genes, and researchers believe that a loss of several of these genesprobably contributes to the characteristic features of this disorder.

_CLIP2, ELN, GTF2I, GTF2IRD1_, and_LIMK1_ are among the genes that are typically deleted in people with Williams syndrome. Researchers have found that loss of the _ELN_ gene is associated with the connective tissue abnormalities and cardiovascular disease (specifically supravalvular aortic stenosis) found in many people with this disease. Studies suggest that deletion of _CLIP2, GTF2I, GTF2IRD1, LIMK1,_ and perhaps other genes may help explain the characteristic difficulties with visual-spatial tasks, unique behavioral characteristics, and other cognitive difficulties seen in people with Williams syndrome. Loss of the _GTF2IRD1_gene may also contribute to the distinctive facial features often associated with this condition.

Researchers believe that the presence or absence of the_NCF1_gene on chromosome 7 is related to the risk of developing hypertension in people with Williams syndrome. When the _NCF1_ gene is included in the part of the chromosome that is deleted, affected individuals are less likely to develop hypertension. Therefore, the loss of this gene appears to be a protective factor. People with Williams syndrome whose _NCF1_gene is not deleted have a higher risk of developing hypertension.

The relationship between other genes in the deleted region of chromosome 7 and the signs and symptoms of Williams syndrome is unknown.

Most cases of Williams syndrome are not inherited, but occur as random events during the formation of reproductive cells (eggs or sperm) in a parent of an affected individual. These cases occur in people with no history of the disorder in their family.

Williams syndrome is considered an autosomal dominant condition because one copy of the altered chromosome 7 in each cell is sufficient to cause the disorder. In a small percentage of cases, people with Williams syndrome inherit the chromosomal deletion from a parent with the condition.

Other names for Williams Syndrome are:

Beuren syndrome

Elfin Facies Syndrome

Elfin facies with hypercalcemia

Hypercalcemia-Supravalvar Aortic Stenosis

Infantile hypercalcemia

Supravalvar aortic stenosis syndrome

WBS

Williams-Beuren Syndrome

WMS

WS

**Wilms Tumor**

Wilms tumor is a childhood form of kidney cancer with a peak age of occurrence at 3 years of age. It is sometimes associated with abnormalities of the urinary tracts or other birth defects. Some cases are related to defects in one of two genes referred to as Wilms' tumor 1 (WT1) or Wilms' tumor 2 (WT2). Symptoms can include abdominal pain, swelling, and blood in the urine. Diagnosis is made by biopsy, which can classify the tumors as having a favorable histology (microscopic appearance) or an unfavorable histology, which is associated with a worse outcome. The outcome is also reflected by the stage of the tumor (extent of spread) at the time of diagnosis. Treatment involves surgery and chemotherapy; sometimes radiation therapy is also recommended. Wilms tumor has a very high cure rate, particularly when detected as a localized tumor. Also known as nephroblastoma.

**Wiskott-Aldrich Syndrome**

Wiskott-Aldrich syndrome (WAS) is a rare hereditary immune deficiency with recessive inheritance linked to the X chromosome (Xp11.22-p11.23). This syndrome is characterized by the association of thrombocytopenia with small-sized platelets, eczema and repeated infections. The deficiency occurs early in childhood, during the first decade and usually before the age of 3 years. Several clinical signs can orientate this diagnosis. The subject is a young boy with hemorrhagic signs (purpura, petechiae, ecchymoses, epistaxis, bloody diarrhoea or others), recurrent infections (bronchial, pulmonary), ENT (ear, nose, throat), eczema and, sometimes, signs of autoimmunity. Children with WAS should be followed in paediatric centres specialized in immunology and haematology. Management consists of treating and preventing infections. When the thrombocytopenia is very severe, splenectomy may be beneficial. Only a bone-marrow transplantation can cure this pathology. Thanks to the characterisation of the gene responsible for WAS, when the mutation has been identified in the kindred, an early antenatal diagnosis can be made at 11 weeks amenorrhea with a trophoblastic biopsy. In familial forms (more than one individual affected), polymorphic markers linked to the disease locus can also be used to evaluate the risk for a pregnant woman to transmit the disease or to perform an antenatal test.

**Wolff-Parkinson-White Syndrome**

Wolff-Parkinson-White syndrome is a condition characterized by abnormal electrical pathways in the heart that cause a disruption of the heart's normal rhythm (arrhythmia).

The heartbeat is controlled by electrical signals that move through the heart in a highly coordinated way. A specialized cluster of cells called the atrioventricular node conducts electrical impulses from the heart's upper chambers (the atria) to the lower chambers (the ventricles). Impulses move through the atrioventricular node during each heartbeat, stimulating the ventricles to contract slightly later than the atria.

People with Wolff-Parkinson-White syndrome are born with an extra connection in the heart, called an accessory pathway, that allows electrical signals to bypass the atrioventricular node and move from the atria to the ventricles faster than usual. The accessory pathway may also transmit electrical impulses abnormally from the ventricles back to the atria. This extra connection can disrupt the coordinated movement of electrical signals through the heart, leading to an abnormally fast heartbeat (tachycardia) and other arrhythmias. Resulting symptoms include dizziness, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, and fainting (syncope). In rare cases, arrhythmias associated with Wolff-Parkinson-White syndrome can lead to cardiac arrest and sudden death. The most common arrhythmia associated with Wolff-Parkinson-White syndrome is called paroxysmal supraventricular tachycardia.

Complications of Wolff-Parkinson-White syndrome can occur at any age, although some individuals born with an accessory pathway in the heart never experience any health problems associated with the condition.

Wolff-Parkinson-White syndrome often occurs with other structural abnormalities of the heart or underlying heart disease. The most common heart defect associated with the condition is Ebstein anomaly, which affects the valve that allows blood to flow from the right atrium to the right ventricle (the tricuspid valve). Additionally, Wolff-Parkinson-White syndrome can be a component of several other genetic syndromes, including hypokalemic periodic paralysis (a condition that causes episodes of extreme muscle weakness), Pompe disease (a disorder characterized by the storage of excess glycogen), and tuberous sclerosis (a condition that results in the growth of noncancerous tumors in many parts of the body).

Wolff-Parkinson-White syndrome affects 1 to 3 in 1,000 people worldwide. Only a small fraction of these cases appear to run in families.

Wolff-Parkinson-White syndrome is a common cause of an arrhythmia known as paroxysmal supraventricular tachycardia. Wolff-Parkinson-White syndrome is the most frequent cause of this abnormal heart rhythm in the Chinese population, where it is responsible for more than 70 percent of cases.

Mutations in the PRKAG2 gene cause Wolff-Parkinson-White syndrome.

A small percentage of all cases of Wolff-Parkinson-White syndrome are caused by mutations in the PRKAG2 gene. Some people with these mutations also have features of hypertrophic cardiomyopathy, a form of heart disease that enlarges and weakens the heart (cardiac) muscle. The PRKAG2 gene provides instructions for making a protein that is part of an enzyme called AMP-activated protein kinase (AMPK). This enzyme helps sense and respond to energy demands within cells. It is likely involved in the development of the heart before birth, although its role in this process is unknown.

Researchers are uncertain how PRKAG2 mutations lead to the development of Wolff-Parkinson-White syndrome and related heart abnormalities. Research suggests that these mutations alter the activity of AMP-activated protein kinase in the heart, although it is unclear whether the genetic changes overactivate the enzyme or reduce its activity. Studies indicate that changes in AMP-activated protein kinase activity allow a complex sugar called glycogen to build up abnormally within cardiac muscle cells. Other studies have found that altered AMP-activated protein kinase activity is related to changes in the regulation of certain ion channels in the heart. These channels, which transport positively charged atoms (ions) into and out of cardiac muscle cells, play critical roles in maintaining the heart's normal rhythm.

In most cases, the cause of Wolff-Parkinson-White syndrome is unknown.

Most cases of Wolff-Parkinson-White syndrome occur in people with no apparent family history of the condition. These cases are described as sporadic and are not inherited.

Familial Wolff-Parkinson-White syndrome accounts for only a small percentage of all cases of this condition. The familial form of the disorder typically has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the condition. In most cases, a person with familial Wolff-Parkinson-White syndrome has inherited the condition from an affected parent.

Other names of Wolff-Parkinson-White Syndrome are:

Ventricular pre-excitation with arrhythmia

WPW Syndrome

**Wolfram Syndrome**

Wolfram syndrome is a genetic neurodegenerative disease that leads to many different abnormalities including diabetes insipidus (inability to concentrate the urine), diabetes mellitus (the usual type of diabetes), blindness (due to optic atrophy, degeneration of the nerve to the eye), and deafness. Patients usually also suffer from severe abnormalities of the nervous system that can be accompanied by behavior problems, psychiatric hospitalizations and, in about a quarter of cases, suicide attempts.

Wolfram syndrome is sometimes referred to as "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Only the insulin-dependent diabetes mellitus and optic atrophy are necessary to make the diagnosis.

The syndrome is inherited as an autosomal recessive trait so that brothers and sisters of a child with the syndrome each have a 25 percent chance of receiving the gene from both parents and therefore having the syndrome. The syndrome is caused by a mutation in the gene responsible for the production of a protein called wolframin, resulting in loss of function of this protein. The gene is in chromosome 4p16.1.

Wolfram syndrome is genetically heterogeneous (mixed). There is, for example, a type of Wolfram syndrome with additional atypical features such as profound upper gastrointestinal ulceration and bleeding as well as an absence of diabetes insipidus. The gene for this type of Wolfram syndrome is not in the region of chromosome 4p16.1 but rather is in chromosome 4q22-24.

**Wolman Disease**

Wolman disease represents the most severe manifestation of lysosomal acid lipase deficiency. Milder phenotypes as a whole are referred to as cholesterol ester storage disease (see this term). The acid lipase enzyme plays an essential role in lysosomal hydrolysis of both esterified cholesterol and triglycerides of lipoproteic origin. In Wolman disease, the rarest form of acid lipase deficiency, these lipids accumulate in most tissues. Approximately 50 cases have been reported in the literature. The disease can sometimes present in the fetus (hepatomegaly, ascitis, calcified adrenal glands), but onset more typically occurs in the first weeks of life with abdominal distension and major or even massive hepatosplenomegaly (which can occur in the neonatal period) and sometimes ascitis. The presence of calcified adrenal glands (as revealed by radiography), is a nearly constant and very characteristic sign. Myelograms reveal the presence of foamy histiocytes, but this is not a specific findings. Children present with significant digestive disorders (such as vomiting and diarrhoea with steatorrhoea), which can lead to a sudden arrest of ponderal growth and progressive psychomotor degradation in the absence of specific neurological signs. Later, severe anemia and cachexia become apparent. Few children survive beyond one year of age. The disease follows an autosomal recessive pattern of inheritance. The enzymatic deficiency results from severe mutations of the acid lipase gene (LIPAor _LAL_), localised to 10q24-q25. The diagnosis can be rapidly confirmed by measuring enzymatic activity in leucocytes (or fibroblasts), revealing an almost total deficiency. Prenatal diagnosis can be performed by measuring enzymatic activity or by mutational analysis of chorionic villus samples. At present, there is no specific treatment available for Wolman disease. However, in two published cases, a very early bone marrow or cord blood transplant seemed to provide good results after a 4-year follow-up. Although enzyme substitution and genetic therapy have shown promising results in the mouse _LAL_ gene knock-out model, these studies can not necessarily be applied to Wolman disease as the mouse phenotype is closer to that of cholesterol ester storage disease.

**Yang deficiency**

Yang represents the energy that is responsible for warming and activating bodily functions. When this energy is depleted your body begins to slow down, displaying signs of under activity and sensations of coldness.

Some symptoms are:

Sore lower back

Copious, pale urine

Cold limbs

Dislike cold

Weak legs

Water retention in the legs

Poor appetite

Loose stools

Infertility

Sexual dysfunction

Premature ejaculation

Chronic vaginal discharge

Loose teeth

**Related Conditions**

Chronic nephritis

Low back pain

Sexual dysfunction

Chronic urinary and prostate problems

Chronic ear disorders

Adrenal fatigue

Hypothyroidism

Depression

Erectile dysfunction

**Foods Used For Yang Deficiency**  
These are just some of the foods that are believed to help Yang deficiency

Lobster

Sardines

Shrimp

Clove

Dill seed

Fennel

Pistachio

Raspberry

Nuts

**Ying deficiency**

Yin is, as understood in Chinese medicine, responsible for organic liquids and anchor the yang. If Yin becames weak then we assist to an increase of Yang in the way that a clinical pattern of yin deficiency will be characterized by the following symptoms:

Agitation: a person cannot be quiet, feel more agitated than normal because there is the rise of yang. Agitation can be internal or external and divided into 2 aspects: physical and/or mental. If the yin deficiency affects the liver symptoms of irritability can occur.

Insomnia: This symptom can be characterized by an initial difficulty in falling asleep (blood deficiency), waking up repeatedly during the night (yin deficiency), or waking too early without feeling you have rested enough and unable to go back to sleep . Yin represents night and reassembles during the night. With yin deficiency, there is an increase of yang that make it difficult to sleep the patient causing insomnia. The characteristics of insomnia duo to Yin deficiency are characterized by waking up several times during the night, and difficulty sleeping a feature of blood deficiency .

Heat : A complex of symptoms exactly symmetrical cold complex symptoms such as warm hands and feet, warm feeling in the body, worsening with exposure to heat, heat intolerance. The decrease of yin leads to an increase in body heat, particularly the hands and feet. It is often argued that the patient could not sleep well and had to put their feet outside the blanket.

Afternoon fever: an increase in body temperature, with the development of fever, the evening is an indication of yin deficiency and is a very common symptom that can be detected on the thermometer. The person with yin deficiency will suffer an increase in temperature as the day goes, contrary to yang deficiency where the temperature of the person tends to fall throughout the day.

Night sweats: loss of body fluids during the night indicates a yin deficiency pattern. It is considered a symptom of heat. The yin deficiency stimulates yang hyperactivity that yin cannot control. As such the fluids are taken by Yang to the outside world being driven off as sweat. There is also the importance of this association with other symptoms such as feeling hot, physical and mental agitation, insomnia, etc…

Dry mouth and throat: a lack of yin to moisten the body end up causing a sensation of thirst and impression of dry mouth and throat. In more severe cases may be the desire to drink cold liquids but in small quantities. When dryness symptoms are accompanied with mucosal lesion with desire to drink cold drinks in quantity and an aversion to hot drinks it is assumed that there was a pattern of fullness heat.

Dark urine and in small quantities is common when there is yin deficiency affecting the kidneys. Constipation is also a symptom of Yin deficiency.

Red face: a sign of heat that both exist in a yin deficiency pattern as in other heat patterns like wind-heat and damp-heat.

Red tongue: it arises in situations of yin deficiency and fullness heat, however, the yin deficiency does not have tongue coating and in patterns of fullness heat there is coated with yellow fur.

Fine pulse, shallow and fast: the fine pulse is indicative of a deficiency pattern, while the features, fast and shallow, indicate a condition of heat. The characteristic shallow, does not indicate, in this case, the location of the nature of the disease. Because yin is weakened, yang tends to come up to the surface. Care is needed in the assessment of cases. For example, a flu, which is a penetration of wind-cold, tends to have a superficial pulse. This happens because the Wei Qi (defensive Qi) swells to the surface to fight the cold and pulse feels superficial.

Chapter 3 is finally done… I finally finished the 203 paged list of diseases! I'm so proud of myself. This proves to be educational… I hope. Well, imōto-chan… hope this helps you with your test or project thing. Just read really fast if you wanna get through all of them in like two days… Well, just a little question here, has there ever been a 204 paged chapter? For people who hate freakishly long chappies, don't worry. This is the only super long chapter that I'll ever write.


	4. Chapter 4

Blood of the innocent chapter 4

Disclaimer: I do not own Naruto or any other anime I use. Well… I only own my OC's and Skye-chan.

After Sasori left, Itachi stared at Ken. Ken saw the stare and looked confused.

"What?" he asked. Itachi just shook his head. Suddenly, the base started shaking like an earthquake was attacking or something. Ken's eyes widened and he ran towards his and Sasuke's room, Itachi following close behind. Ken threw open the door to see that Sasuke was crying. His voice wasn't very big, but it was loud enough to do damage. Ken quickly ran towards his side and picked him up, attempting to stop his cries.

"Shhh… Shhh… Sasu-chan, it's okay. It's okay, Sasu-chan. Stop crying, please." He said, trying to calm him down, but Sasuke kept on crying. Itachi saw this and gently took his brother from Ken and poked his forehead like he did when they were still kids. This immediately stopped Sasuke's cries, his eyes still not open. Itachi patted Sasuke's head and Sasuke clung to his brother like he was his lifeline.

"It's alright, Sasuke. Your nii-san is here. No more crying, Sasuke." He said. Sasuke nodded and calmed down some more. Ken sighed.

"Sasu-chan, what happened?" he asked. Sasuke buried his head in Itachi's neck and whimpered quietly. _Scary… it's scary!_ He said. Itachi looked confused.

"What's so scary, otōto?" he asked. Sasuke started shaking slightly. _Nii-san's disease is scary!_ He cried, tears flowing out again. Itachi sighed and wiped away Sasuke's tears.

"Sasuke, you know I can't make my disease go away no matter how much I do." He said. Sasuke tilted his head up to his brother. _I can make nii-san's disease go away. Then nii-san won't be in pain anymore._ He said. Itachi looked surprised.

"You really can?" he asked. Sasuke nodded. _ If it's for nii-san, then I can do it._ He said. Itachi smiled and nodded.

"Alright. It's only if you want to do it though." He said. Sasuke smiled and nodded. _I want to help nii-san!_ He said happily. Itachi chuckled and nodded. Suddenly, all the Akatsuki members burst into the room.

"What the f*ck just happened here? The f*cking ground was shaking like sh*t!" Hidan yelled. Kakuzu looked around the room and saw Sasuke, who had just finished crying.

"Was it him?" he asked, gesturing to Sasuke. Ken nodded.

"Hai… sorry about that. It's not his fault though. He was scared." He said. Konan looked worried.

"What was he scared of? And how could he make the whole base shake like there was an earthquake?" she asked. Ken sighed.

"I'm not sure what he was so scared about, but if I tell you how he could do that, then you have to promise to never tell anyone else." He said seriously. The members saw his seriousness and nodded.

"Alright. We won't tell anyone." Pein promised. Ken nodded and started telling them about Sasuke's ability.

"Well, you see… Sasu-chan is really powerful, and since he's so small, his body can't handle that much. So in order to counter that, his body sent most of his power to his eyes and vocal cords. That's the reason he's not allowed to speak or see unless in an emergency. When 'they' found out at Deadman Wonderland that Sasu-chan's eyes and vocal cords were so powerful, they wanted the power all to themselves, so they created the punishment game. They set the machine specifically to land on vocal cords for Sasu-chan. And they purposefully decided to take my eyes because they knew that Sasu-chan would try and protect me. That was all part of their plan, but what they didn't know was that once they were removed, the power in them returned to Sasu-chan. They would stay dormant until Sasu-chan grows new eyes and vocal cords." He said. When he finished, the whole Akatsuki were gawping at them, and more specifically, Sasuke. Sasuke felt the stares and buried his face into Itachi's neck, trying to hide. Itachi chuckled and pat Sasuke's head.

"It's alright, otōto. We'll protect you." He reassured. Hidan scoffed.

"Who said I was going to help? The little sh*t can die for all I care." He said. Itachi, Ken, and Konan glared at the Jashinist.

"You will help protect him, Hidan. These are orders now. Everyone is to protect Sasuke at all costs." Pein said. Hidan glared and tsked, but said no more. Sasuke, who was clinging to Itachi, held on even tighter.

"What's wrong, Sasuke?" Itachi asked. Sasuke hugged Itachi a bit tighter. _Nii-san, am I a nuisance to you? Would it be easier if you didn't have to protect me?_ He asked. Itachi sighed.

"Sasuke, you are not a nuisance. I will admit that it would be easier if we didn't have to protect someone all the time, but since you're my otōto, it's worth the trouble." He said. Sasuke got tears in his eyes, though no one saw. '_I understand… I'll just disappear so nii-san doesn't have to go through the trouble. I'll also make it so nobody remembers me, so no one would worry. Mm, that would work. But first, I'll cure nii-san's disease.'_ He thought.

"Alright, everyone just go back to doing what you were already doing." Pein ordered and walked out of the room, no one knowing of Sasuke's thoughts. Sasuke lifted his head and placed his hand on Itachi's chest, his hand glowing a sky blue. Itachi looked confused.

"Sasuke, what are you doing?" he asked. Sasuke smiled. _Healing nii-san._ He said. Itachi smiled.

"Arigato, Sasuke." He said. Sasuke shook his head. _Don't thank me yet. I'm not even done yet._ He said, and he gave a silent gasp a second later. _Nii-san, when did you get __Lymphangioleiomyomatosis?_ He asked. Itachi looked confused.

"What are you talking about, otōto?" he asked. Ken took Sasuke's hand so he could hear what he was saying. Sasuke looked worried. _Nii-san, you have a really rare disease called Lymphangioleiomyomatosis. It usually only affects woman, but men can get it too. There are less than one in one million that have it, so not much is known about it._ He said. Ken looked worried.

"Is there a treatment for this?" he asked. Sasuke nodded and smiled. _Hai. The treatment is a double lung transplant. Though it's going to be really hard finding a set of lungs. They have to have the same blood type and since nii-san is an Uchiha who specializes in Katōn no jutsu, they have to be an Uchiha as well._ He said. Ken gasped and his eyes widened.

"S-sasu-chan, you aren't going to… are you?" he asked. Sasuke nodded. _It's the only way nii-san can be cured. I don't care about anything else. Just let nii-san get better._ He said. Itachi smiled, not knowing what Sasuke was thinking about. Ken sighed.

"Alright, but you'd better be alright after this. I'm not going to stand you getting hurt." He said. Sasuke nodded. _It's not like I'm going to die healing nii-san._ He said with a smile. Little did Itachi know, Sasuke would die in the procedure. Itachi smiled and kissed Sasuke's forehead.

"Be careful though, okay?" he asked. Sasuke nodded and started the healing process, secretly severing his lungs and replacing Itachi's lungs with his own. Once he was finished, Sasuke was panting and fell limp in his brother's arms. Itachi found it easier to breathe, but when Sasuke went limp, he immediately panicked.

"Sasuke? Sasuke! Wake up, Sasuke!" he begged, gently shaking his brother. Ken stood back, looking on regretfully.

"Itachi-san, he's dead. Sasu-chan is dead." He said. Itachi glared at him.

"How do you know? How do you know that he isn't just unconscious?" he asked. Ken sighed.

"Sasu-chan is strong enough that he won't faint after curing a disease. You feel that it's easier to breathe, don't you?" he asked. Itachi nodded.

"What did Sasu-chan say the cure is?" he asked. Itachi's eyes widened and he fell to his knees, hugging his brother's body close to him.

"Why? Why didn't you stop him if you knew?" he asked. Ken sighed regretfully.

"That was what Sasu-chan wanted. I couldn't stop him even if I wanted to. He made it so I couldn't move. Also, did you hear his thoughts earlier? He was planning on committing suicide so you wouldn't have to 'go through all the trouble' protecting him." He said. Itachi let out silent tears, holding in the sobs.

"Why? Why did he do this to himself?" he asked. Ken was about to reply, but was cut off by a bright flash of light. Once the light dimmed, he made out a figure of two girls. His eyes widened when he realized who they were.

"Skye-chan! Aoi-chan!" he cried. The two looked towards him and smiled. Now an overview of what the girls look like. Skye was pretty tall, about the height of Ken. She had light caramel colored skin, light brown eyes, and long hair in a braid. She was wearing black robes and has a pair of pure black wings. She was also holding a large black scythe. Yes, Skye was the angel of Death, but not just any angel of Death. She was the ruler and guardian of Jigoku. Next is Aoi. She was about the same height as Itachi. She had flowing long blood red hair cascading down her back and crystal blue eyes. She was wearing white robes which greatly contrasted with her hair and she was holding a staff with a small crystal ball at the top. Aoi was the ruler and guardian of Tengoku.

"Yo. So, he finally did it?" Skye asked. Ken sighed and nodded.

"Hai, and I couldn't do anything to stop him." He said regretfully. Aoi sighed.

"Well… stop being so gloomy. It's not like he's completely dead yet. His soul is still here. It seems like he doesn't want to leave his brother." She said. Itachi heard this and looked up at her hopefully.

"He isn't dead yet? Can he come back?" he asked. Skye smirked.

"Sure he can. That's what we're here for. Kōri-hime sent us here to bring him back. And before you ask, no we do not hate each other. We're both guardians of Kōri-hime, so we get along." She said. Aoi laughed.

"Skye-chan, you're so straightforward." She said. Skye smirked.

"Heh, and you're not?" she asked. Aoi giggled.

"Touché." She said. Skye scoffed and shook her head.

"Well, let's get this show on the road." She said. Itachi stared at both of them.

"Ummm… who's Kōri-hime?" he asked. Ken stared at him.

"You don't know?" he asked. Itachi shook his head and Ken sighed.

"She's the sōzō-sha. In other words, the creator of the world and every single form of energy. Without her, the world wouldn't exist and there wouldn't be the five elemental countries or shinobi. If you guys call God the creator of humans, then Kōri-hime would be the great grandmother of God." He said. Skye snickered.

"Ah, Kōri-hime would kill you if she heard that." She said. Ken shrugged and gestured to Sasuke.

"Don't you wanna do your job?" he asked. Aoi nodded and went over to Sasuke's body. She caressed his face in her hand and looked to where Sasuke's spirit was.

"Sasu-chan, don't you want to be with your brother?" she asked. Sasuke nodded. Aoi smiled.

"Then why did you leave him?" she asked. Sasuke lowered his head. _If I stayed, then nii-san would have to go through trouble. I also wanted to heal him. This was the only way, wasn't it? _He asked. Aoi shook her head.

"Sasu-chan, I'm sure that Itachi-kun doesn't think that it'll be trouble protecting you. Also, that wasn't the only way to heal him. You could have just called for us and we would've come to help. I know Kōri-hime would have said the same thing." She said. Sasuke started crying. _But I don't want to trouble nii-san. It's all my fault that nii-san had to leave Konoha. If Danzō didn't know about me, then he wouldn't have created Deadman Wonderland and ordered nii-san to kill the clan! It's all my fault!_ He cried. Aoi sighed and shook her head. She turned to Itachi and smiled.

"Itachi-kun, do you think it's Sasu-chan's fault that you left? Do you think that he'll cause you trouble if he stayed?" she asked. Itachi's eyes widened and he shook his head quickly.

"Of course not! He's my otōto. He'll never cause me trouble, and even if he does, I'll like it. If it's for him, then it's all worth it. And why would he think that it's his fault that I killed the clan?" he asked. Aoi shook her head.

"He thinks that if he was never born, then all this wouldn't have happened. Since Danzō created Deadman wonderland for him, he thought that it was because of him that Danzō ordered you to kill your Clan." She said. Itachi looked stupefied.

"What Danzō ordered me to do has nothing to do with Sasuke. He isn't the one at fault." He said. Aoi smiled and turned back to Sasuke's spirit.

"See? He doesn't think that it's your fault." She said. Sasuke shook his head. _He's lying. He thinks that it's my fault. If I was never born, then this never would've happened!_ He cried. Aoi sighed again.

"How about this. You come back and if you can prove that Itachi-kun is lying, then we'll take you. Okay?" she asked. Sasuke looked up at her. _Really?_ He asked. Aoi nodded and Sasuke smiled. _Alright. I'll come back, but do I really have to prove that nii-san is lying?_ He asked. Aoi inwardly smirked and shook her head.

"No, you don't. Just come back and make your nii-san happy." She said. Sasuke nodded and smiled. _Hai… but how? My body's already all dead and stuff._ He said. Skye smirked and leaned down to his level.

"That's what we're here for. Now get back in your body and let us heal you." She said. Sasuke smiled and nodded, walking over to his body and laid down in it. Aoi and Skye smiled and clapped their hands twice.

"Fukkatsu!" they said and a bright light kinda went 'boom' and then died down. When everyone could see again, Sasuke was sitting up and clinging to Itachi, nuzzling his cheek with his own. Itachi's eyes were wide and he hugged back tightly.

"Sasuke! Don't you ever do that again, you hear me?! I don't ever want to lose you again!" he cried. Sasuke smiled and nodded. _Hai, nii-san. Can you tell Aoi-chan and Skye-chan 'thank you'?_ He asked. Itachi nodded and smiled. He turned to Aoi and Skye and bowed.

"Arigato-gozaimasu, Aoi-san, Skye-san. Sasuke would've died if you weren't here." He said. Aoi smiled and Skye shook her head.

"Well… in a way, he's still dead. He has no lungs. We'll have to give him a pair later. But for now, he's just fine. If he has any breathing problems, just call us using this. Just look into the mirror and call our names. Or you can just call Kōri-hime and she'll help you too." Skye said, handing Itachi a small compact mirror and showing him how to use it. Itachi took the mirror and nodded, smiling.

"Arigato-gozaimasu." He said. Aoi and Skye sighed.

"That's your second time saying that… stop thanking us and start tending to your brother." Aoi said. Itachi looked confused, but when he saw that Sasuke was trying to breathe, he started panicking.

"W-what do I do?" he asked. Skye sighed.

"All you have to do is give him oxygen. This is gonna be goin' on for a while now. Since he has no lungs, you'll have to get used to the process of giving him air to breathe. Now watch closely." She said as she took out an oxygen mask and placed it over Sasuke's mouth and nose. Itachi watched as Skye did that and how Sasuke started to breathe easier after that.

"You got that?" Skye asked. Itachi nodded and Skye handed him the box. Skye pointed to the box.

"This is an oxygen generator. You have to put the mask on him first, and then turn it on by flipping the switch. It'll give him oxygen and he'll be able to breathe okay. Just know that if he doesn't get air within fifteen minutes, he'll go unconscious, and then he'll die within the next twenty minutes." She said. Itachi's eyes widened and he nodded quickly, placing a hand on the mask on his brother. He looked down at his brother, who was now sleeping peacefully.

"Sasuke, what are you thinking?" he asked. Aoi and Skye shrugged.

"He thinks about a lot of things. Usually though, it's about how to help you." Ken said. Itachi looked up at him with wide eyes.

"He thinks about me?" he asked. Ken nodded.

"He told me a couple times that he's worried that you'll get hurt and die someday. He's afraid that if you die, he won't be by your side and that you'll die alone. Basically, he's just worried that you'll get hurt and die alone." He said. Itachi nodded and gently stroked Sasuke's head.

"I see. But why would he worry so much about me when he's the one who's at the risk of dying any second?" he asked. Ken shrugged.

"Well, I'm guessing that he wants his family to live. Since you're his last living relative that's blood related, he wants to protect the bond between you and him." Aoi said. Itachi sighed.

"I can understand wanting to protect the bond between us, but why is he going so far to do so? It's not like our bond is just going to snap any second." He said. Skye shook her head.

"Now that's where you're wrong." She said. Itachi looked up at her, confused.

"Sure bonds between family are hard to break, but they are also very fragile. Sasuke's been locked up in an h*ll almost all his life. His only bond was with Ken and the other Deadmen there. The only bonds he had were friend bonds, not family bonds. And he only got a family bond between you and him recently, so it's more fragile than ever. It can be broken easily, so he wants to protect that." Skye explained. Ken nodded.

"That's true. Now that I think about it, Sasu-chan never smiled at Deadman Wonderland. Everyone else there has smiled at least three times, but Sasu-chan never smiled. Not even once." He said. Aoi nodded.

"It makes sense for him not to. He was burdened with so much. Taken away from his family when he was three, stayed there for most of his Academy life, and the let go for a week. Then they took him back and kept him there until he lost it and destroyed the place. It's not very surprising that he wouldn't smile." She said. Itachi sighed and looked at Sasuke sadly.

"Why did it have to be him?" he asked. "Why did it have to be him to suffer so much? I would've been happy if it were me to be in his place, or even to just be by his side." Ken sighed and shook his head.

"Well… enough of this depressing talk. Skye-chan, Aoi-chan, please tell Kōri-chan 'thank you'." He said. Aoi and Skye nodded, and then disappeared in a flurry of feathers. Ken sighed and looked down at Sasuke.

"Itachi, you should probably take off the mask. Sasu-chan looks like he's about to barf…" he said. Itachi looked at Sasuke, who looked kinda green, and took off the mask. Sasuke coughed a little and sat up. Itachi smiled and poked Sasuke's nose, making him sneeze. Ken squealed and hugged Sasuke.

"KAWAII!~" Sasuke squirmed a bit and quietly whined. Itachi smiled at the sight and pulled his brother from Ken's death grip. Sasuke immediately clung to Itachi and nuzzled his face. Ken pouted and crossed his arms.

"So mean…" he grumbled. Sasuke quietly laughed and poked Ken's side, making him squeak.

"Eep! Sasu-chan! That was so mean! You know that I'm ticklish…" he whined. Itachi chuckled and shook his head.

"You two never cease to amuse me." He said. Sasuke smiled and Ken pouted. Itachi patted Sasuke's head and Sasuke coughed a bit again. Ken patted Sasuke's back and Sasuke coughed harder. Itachi placed his hands on Sasuke's stomach from behind and pushed on Sasuke's stomach. Sasuke started coughing harder and finally coughed out a pretty large puddle of blood. When that was done, Sasuke sighed in relief and smiled. Ken wiped the blood from Sasuke's mouth and Itachi looked panicked.

"Sasuke, are you okay? What happened?" he asked. Sasuke shrugged.

"It's just excess blood that Sasu-chan doesn't need." Ken explained. Itachi nodded and steadied Sasuke when he started falling. Itachi looked worried and shook his brother a bit.

"Sasuke? Sasuke, wake up. Sasuke!" he called. Sasuke didn't respond. Ken looked at the young Uchiha and then to Itachi.

"Itachi, how long have we been here?" he asked. Itachi looked confused.

"About four days. Why?" he asked. Ken cursed and sighed.

"He fell asleep. There's no telling when he'll wake now." He said. Itachi was worried. Ken knew and went to Sasori's room and knocked. Sasori opened the door and stared at Ken.

"What is it?" he asked. Ken sighed.

"Have you memorized the scroll?" he asked. Sasori looked confused, but nodded.

"I have, why?" he asked. Ken pointed to Itachi's room.

"We need you to see if Sasu-chan has a disease that's in the scroll. He fell asleep again." He said. Sasori nodded and followed Ken to Itachi's room. When they went in the room, Itachi was cradling Sasuke to him and looked up at Sasori and Ken.

"Sasori-san?" he asked. Sasori nodded and knelt down next to Sasuke. He did a basic check up and then stood up.

"I'm not one hundred percent sure, but I think that he has Klein-Levin Syndrome." He said. Itachi looked confused.

"Klein-Levin Syndrome?" he asked. Sasori nodded.

"Hai. It's a disease that makes you sleep for extended periods of time without waking. I can't recite all the details, but that's basically it." He said, and then looked to Ken.

"You said that he usually stayed awake for a couple days, and then slept for around a year right?" he asked. Ken nodded and Sasori sighed.

"I'm afraid that I can't do anything for that. I also think that the jutsu I used on him to lessen the time did not work that much." He said. Ken sighed.

"I was afraid of that." He mumbled, and then shrugged. "Now the hard part is to get him to eat and drink. He'll die if he doesn't do either for a year or month or however long he's asleep." Itachi nodded. Sasori shrugged.

"I might be able to help with that. All you have to do is massage his throat to loosen it up and then feed it to him. Ken-san said that Sasuke-kun can't have solids, so he can only have liquids, right?" he asked. Ken nodded.

"Then I'll make something that has the nutrition's that he's lacking." Sasori said. Ken nodded and smiled.

"Arigato, Sasori-kun." He said. Sasori waved his hand in dismissal.

"It's fine. Consider this my payment for the scroll." He said. Ken smiled.

"Sure, though the scroll was free." He said. Itachi looked at Sasuke with worried eyes.

"What if he never wakes up?" he asked. Ken and Sasori looked down at him and Ken sighed.

"He'll wake up. We have to wait for him. Oh, and Sasu-chan's vocal cords and eyes have re-grown. It seems that Skye-chan's and Aoi-chan's power have sped up the healing process." He said. Itachi brightened up a bit and smiled.

"He'll finally be able to see and speak again." He said quietly. Ken nodded.

"I finished making the contacts too." He said. Itachi nodded and hugged Sasuke close to him.

"Now all we have to do is wait for him to wake up." Sasori said as he left the room. Ken sighed.

"Sasu-chan, wake up soon. Your brother's gonna go all Bazinga if you don't." He said. Itachi smiled and brushed away a few strands of hair from his brother's face.

Okay… crappy chapter, but deal with it. I couldn't think of anything else to write and this was the first idea that came to mind. Well, chapter 4 is now done.


	5. Chapter 5

Blood of the innocent chapter 5

Disclaimer: I do not own any of the anime I use in this thing. I only own my OC's and Skye-chan. I'm sorry for not updating in a while. My brain decided to be a butt and die on me, so I had a dysfunctional brain… and I was updating my freakishly long list of rare diseases. Anyways, Gomenasai!

It's been four days since Sasuke had fallen 'asleep' and he still had yet to wake up. Itachi was getting more worried each day and Ken kept trying to calm him down in case he went all murderous-rampage-mode.

"Itachi, you should calm down a bit. It's only been four days. The longest he's ever slept was six months. I doubt that it'll happen again." Ken said. Itachi didn't listen and kept on pacing back and forth waiting for Sasuke to wake up. Ken sighed and dragged Pein over.

"Pein-sama, do us all a favor and stop him before he paces a hole in the base?" he asked. Pein stared at Itachi and nodded.

"Itachi. Stop. Sit. Calm. Down." He ordered. Itachi stared at the Akatsuki leader and glared lightly before sitting down on the couch. Pein sighed and went back to his office. Ken sighed as well.

"Look, Itachi. I know that you're worried about Sasu-chan, but he'll be fine. Let's go check up on him if you're so worried." He suggested. Itachi brightened up a bit at that and nodded. The two went to Itachi's room where Sasuke was sleeping. Itachi brushed some hair away from Sasuke's face and felt underneath his nose.

"He's not breathing." He said. Ken nodded and took out the box and mask. Itachi took the mask and placed it over Sasuke's mouth and nose, and then Ken turned on the box. A while after that, Sasuke started breathing normally again and unconsciously grabbed Itachi's hand. Itachi's eyes widened as he heard Sasuke mumble in his sleep.

"Nīsan…" he mumbled quietly. Itachi smiled and pulled Sasuke into an awkward hug.

"Otōto. Wake up soon." He said and kissed Sasuke on the forehead before leaving the room. Ken smiled and ruffled Sasuke's hair affectionately.

"Alright then… sleep well Sasu-chan. Oh, and wake up soon. Your brother's gonna kill someone soon." He said and left the room. After he left, Sasuke started to stir, but didn't wake.

{Five days later}

"Why isn't he waking up?!" Itachi asked. Ken sighed impatiently.

"This is more annoying than I thought it would be…" he mumbled, watching as Hidan started screaming incentives at Kakuzu and became more pissed when said miser ignored him. Ken sighed again.

"Cut it out, will you? If you have nothing to do other than yell at each other, then do us a favor and see if Sasu-chan's awake." He said. Hidan glared at Ken.

"Why the f*ck should we do that?!" he yelled. Ken glared back.

"Let's just say that if you don't, you're risking the whole base being blown to smithereens. You don't want that do you? Just think about how much money it'll cost." He added as an afterthought, catching the attention of Kakuzu. Hidan started screaming his head off as Kakuzu dragged him to Itachi's room to check on Sasuke. When they got there, they saw that Sasuke was still sleeping. Kakuzu sighed and dragged Hidan back to the living room.

"He's still asleep. You might want to check on him though. It seems that he's having trouble breathing." He said. Itachi and Ken's eyes widened and they quickly burst into Itachi's room where Sasuke was sleeping. He still had the mask on, but he was still having trouble breathing. Ken picked up the box and saw that it was out of battery. Ken sighed and dug in his pockets, pulling out two new batteries and replaced them. He then turned off the box and turned it back on. The two watched as oxygen started to fill the mask and how Sasuke started to breathe easier again. Itachi sighed in relief and hugged Sasuke.

"I was so worried…" he said. Ken smiled.

"You still are. Sasu-chan will wake up soon. His breathing pattern's changed." He said. Itachi visible brightened up and smiled a bit.

"I'm so glad." He said. Just as he placed Sasuke back on the bed, Sasuke began waking up. Itachi and Ken watched as Sasuke brought up a fist and rubbed his closed eyes, yawning. Sasuke frowned when he felt the mask and pulled it off, yawning again. Itachi smiled and pulled Sasuke into a hug.

"I was worried, otōto." He said. Sasuke smiled and hugged back.

"I'm sorry." He said quietly. Not a little quiet, but Alice quiet, which is pretty dang quiet. Itachi pulled back in shock.

"S-Sasuke… you talked." He said. Sasuke laughed a bit and nodded.

"Mhmm." He said. Ken smiled and hugged Sasuke as well.

"Sasu-chan, you probably need to train soon. I know that you're still very strong and haven't lost any of your skills, but you need to grasp how to see without killing everyone within a five hundred meter radius." He said. Sasuke pouted but nodded, magically teleporting outside to a forest that was already dead. Since no one was there but him, he wasn't afraid to talk louder or open his eyes, so he did… and the forest within five hundred meters of Sasuke crumbled to the ground. Sasuke silently growled and moved to a different part and tried it again. This time, only the forest within two hundred fifty meters got smashed into the ground. Sasuke sighed again and kept on trying until he finally got it. Finally, on the twentieth try and the third hour, he finally got it. He opened his eyes and said 'hi' in a normal voice, and nothing happened. Sasuke cheered and willed not to crush the people he held dear to him, which included Hidan, Kisame, Kakuzu, Deidara, Sasori, Itachi, Ken, Pein, Konan, and Zetsu. He could care less if Tobi died or not. He was a bad guy after all.

"I finally got it." Sasuke said quietly to himself and walked back to the base. When he went in, everyone stared at him with wide eyes, seeing that his eyes weren't closed. Sasuke sighed, watching as they relaxed a minute later when they realized that they weren't being crushed… well, almost everyone. Tobi started screaming in pain and writhing on the ground, an unknown force pushing him into the ground. Itachi's eyes widened at this and he quickly covered Sasuke's eyes. Once he did that, Tobi fell unconscious when the force disappeared. The rest of the Akatsuki stared in shock at the unconscious hyperactive orange lollipop. Deidara was the first to break the silence.

"What the f*ck, un…" he said. Hidan nodded.

"Yeah. Sasuke just f*cking opened his eyes…" he said. Pein stared at Tobi with semi-wide eyes.

"Sasuke, come with me to my office. Itachi and Ken, you two come as well." He said and walked to his office with Itachi, Sasuke, and Ken following him. Once they were there, Pein stared at Sasuke intently, making him shrink back and hide behind Itachi. Pein sighed.

"Sasuke, what happened?" he asked. Sasuke shook his head, so Ken answered him.

"Well, first off, Sasu-chan opened his eyes. Once he does, it'll destroy everything around him unless he doesn't want it to." He said. Pein nodded, surprised by his power.

"So you're saying that Sasuke didn't want to kill anyone but Tobi?" he asked. Sasuke nodded.

"Tobi is bad. Bad people shouldn't be here." He said quietly. Pein sighed.

"So you know about his true identity?" he asked. Sasuke nodded.

"But he's not who you guys think he is." He said, once again, really quietly. Pein looked surprised, along with Itachi and Ken.

"What do you mean, otōto?" Itachi asked. Sasuke sighed.

**[SPOILER ALERT! THOSE WHO DO NOT WANT THE ANIME TO BE RUINED FOR THEM, STOP READING RIGHT NOW! SAME FOR THOSE WHO HAVE JUST STARTED READING AND/OR WATCHING NARUTO/NARUTO SHIPUUDEN!]**

"I mean, that 'Tobi' isn't Madara." He said. Pein narrowed his eyes.

"Then who is he?" he asked. Sasuke inwardly sighed and made it so that only the things he wanted to destroy will be destroyed and opened his eyes.

"He is Uchiha Obito. It seems that he wasn't killed during the mission and was saved by Madara's ghost and Zetsu. Madara created Zetsu to help him." He said. Pein's eyes were wide, along with Itachi's and Ken's.

"W-what? So all along, we've been fooled by Obito?" Itachi asked. Sasuke nodded.

"Yup." He said. Ken stared at Sasuke with wide eyes.

"Ne, Sasu-chan, how do you know this?" he asked. Itachi and Pein looked at the young Uchiha.

"Yes, we would like to know as well." He said. Sasuke sighed and shrugged.

"Well, Kōri-chan said that since we were really good friends, she'd give me the power of knowledge. She said that I have to use my knowledge to help change the future to a better one than the one that you're making right now. Basically, I now know everything. The past and the future that you have now and the future that I'm going to help you make." He said. Itachi stared at his otōto in shock and awe.

"Otōto, father would be proud." He said. Sasuke smiled and shook his head.

"Nah, not really. If you think about it, he wouldn't really care. Oh, and Skye-nē said that she and Aoi-nē are coming with new lungs or something like that. I wonder why…" he said. Itachi looked sad when Sasuke said that their father wouldn't care about him, but then remembered that Skye and Aoi were coming to give Sasuke new lungs. Itachi hugged his brother tightly and chuckled at his confused expression.

"Skye-san is coming to give you new lungs. Since you gave yours to me to cure the disease, you have a really damaged pair of lungs and it's really hard to live with those." He said. Sasuke ah-ed and nodded.

"I get it now… I think… I hope." He said. Ken laughed and patted his head.

"Don't worry, Sasu-chan. You'll get it when she gets here. And Pein-sama, are there any other questions?" he asked. Pein nodded.

"One more. Sasuke, do you know who I actually am?" he asked. Sasuke nodded.

"Yup. I also know who the person standing in front of us is." He said. Pein stiffened and nodded.

"Very well. You may go." He said. Sasuke sighed.

"I won't tell anyone. I'm not that bad, am I?" he asked. Pein chuckled and shook his head.

"No, no you aren't." He said. Sasuke smiled and walked out of the office with his brother and Ken. When they got back to the living room, Sasuke glomped his brother and nuzzled his face. Itachi looked confused, but hugged back. Ken sighed and shook his head.

"Sasu-chan, what's the matter with you today?" he asked. Sasuke pouted and gave Ken a mock glare.

"Hey, I was asleep for who knows how long. I've been denied nīsan hugging/glomping for that whole time. I think it's okay if I smother him with love for the next few weeks to make up for his missed hugs and glomps." He said. Itachi chuckled along with some other members. Kisame patted Sasuke on the head.

"You've been asleep for a week and two days squirt." He said. Sasuke looked surprised and looked to Ken.

"That short?" he asked. Ken nodded while everyone else looked confused and slightly horrified.

"What do you mean by 'that short'?" Konan asked as she came into the room. Sasuke shrugged.

"I'm usually asleep for a few months…" he said. Konan's eyes widened, along with some other members. Namely Itachi, Kisame, Deidara, Sasori (kinda… not really), and Hidan.

"A few months?!" he screamed. Sasuke nodded.

"Yup. Usually it's like sixty-four days or somewhere around that. The longest I've ever slept was six months." He said. Itachi's eyes were the size of saucers now.

"What?! You've been asleep for half a year?!" he asked, or more like screamed. Sasuke winced slightly and nodded, rubbing his ears.

"Yes?" he said, unsure of how to answer his panicking brother. Itachi hugged Sasuke tightly and buried his face in his hair.

"Otōto, don't scare me like that again. I thought you were dead. And please don't sleep for more than a year… I would like for you to be alive, not dying from hunger and thirst." He said. Sasuke laughed and nodded.

"Hai." He said. Itachi smiled and kissed Sasuke's forehead, making him turn red with embarrassment. Ken and Itachi chuckled while Kisame held back the urge to glomp the living daylights out of Sasuke and squeal like a little girl.

"Yo." A girl said. Almost everyone in the room screamed and fell out of the couches. The girl started laughing and pointed to them.

"My gawd, that was the second best reaction I've ever got!" she exclaimed. Another girl beside her sighed.

"Skye, calm down. We're not here to wreak havoc." She said. Skye tsked and rolled her eyes.

"Fine, Aoi. Being such a spoilsport…" she mumbled and pointed to Sasuke, Itachi, and Ken.

"You three, to Itachi's room. Sasuke get on the bed and close your eyes. It's gonna hurt like a b*tch." She said. Itachi, Sasuke, and Ken all went into Itachi's room and Sasuke sat on the bed with Itachi. Skye and Aoi came into the room shortly and sound proofed it. Skye looked at Sasuke and pushed him down onto the bed.

"Aiight, Sasuke, hold your brother's hand. This is gonna hurt really badly, and by really bad, I mean **REALLY, REALLY **bad. I don't care if you scream, or squeeze your brother's hand off. Just don't move. Relax. It'll help a lot." She said. Sasuke looked nervous and nodded while Itachi was worried. Itachi grabbed his brother's hand and felt Sasuke squeeze it slightly. Itachi squeezed back and watched as Skye took out a box and opened the lid. Inside the box, was a preserved, fresh pair of lungs. It was still moving, so Itachi knew that it was only recently cut out. Skye placed a hand on Sasuke's chest and used the other hand to pick up the lungs. Her hand on Sasuke's chest glowed a bright green and she started making the incision. Sasuke jerked a bit, but then calmed down after. When the slit was large enough, Skye stuck her hand it. Itachi's eyes widened and Sasuke squeezed his hand a bit. Itachi looked at Sasuke's face to see if he was hurting, but his face showed no sign of pain. Only the squeezing of his hand told him that his baby brother was hurting. Skye reached around and finally got a hold of the leftovers of Sasuke's lungs. She started to pull out the remains of what was once his lungs and looked towards Itachi when she heard a small, barely audible gasp from Sasuke.

"Itachi, calm him down, will you?" she asked. Itachi nodded and started whispering comforting words into Sasuke's ears. Sasuke visibly calmed down and Skye quickly finished 'cleaning'. She then took the lungs and inserted them into the young Uchiha. Sasuke sneezed. Itachi chuckled and Skye shook her head, smiling and finishing up the procedure.

"Aiight, I'm done. Now all there is to do is get him to sleep and put the mask on." She said. Itachi stared at her.

"He's going to sleep again?" he asked. Skye sighed and nodded.

"Yes he is. But this time, it'll only be for a little while. Like two days or so." She said. Itachi sighed and kissed Sasuke's forehead as he closed his eyes and fell asleep once again. Aoi brought in the mask and box and put them on Sasuke, watching his reaction. When she saw nothing wrong, she nodded to Skye and the two guardians left. Itachi looked down at his brother and leaned down to press their foreheads together. Itachi smiled.

"Otōto, wake up soon." He said. Ken sighed.

"You're really impatient, aren't you? Skye-chan said this already. Sasu-chan will wake up in a little while. Just give him a few days to get used to having lungs again. He's gone like three weeks without them. He'll need to get used to having them again." He said. Itachi nodded and left the room with Ken.

{The next day}

"Sasuke? Are you awake?" Itachi asked his sleeping brother. When Sasuke didn't answer, Itachi sighed and walked out of the room.

{The day after that}

"Sasuke? Are you awake now? Come on, wake up." Itachi urged. Sasuke still didn't stir. Itachi sighed and decided that if his brother didn't wake up the next day, he would go on a murderous rampage and destroy Konoha for hurting his baby brother.

{The next day}

"Sasuke?" Itachi asked as he entered the room. There was no answer, so Itachi decided to try again, but when he saw the empty bed, he immediately began to panic.

"Sasuke?!" he screamed as he looked around the room. He stopped though, when he heard a sneeze from the living room. Itachi entered to see Sasuke playing with Kisame's sword and Kisame chuckling at the sight.

"Ah, he's so cute…" he sighed dreamily. Itachi smiled and picked up Sasuke, earning a small squeak of surprise. Kisame ran out of the room squealing like a little girl, making the Uchiha brother's sweat drop.

"Sasuke, are you okay? Are you hurt anywhere?" Itachi asked as he looked at Sasuke for any injuries. Sasuke smiled and shook his head, hugging his brother and nuzzling his face.

"Nope. I'm fine." He said. "I missed you, nīsan." Itachi smiled.

"I missed you too, otōto." He said. Sasuke giggled and buried his face in his brother's neck. The two brothers were having the time of their lives, but Ken decided that it would be fun to interrupt their hug fest.

"Hey guys. Oh, Sasu-chan, you're awake. You took like four days to wake up!" he pouted. Sasuke and Itachi both turned to glare at the intruder.

"Ken-nī… you know better than to interrupt at a time like this." Sasuke said in a sickly sweet voice. Itachi glared even harder.

"Ken-san, the next time you do this, you will regret ever being alive." He threatened. Ken gulped and nodded, quickly running out of the room. Once he was gone, Itachi and Sasuke started laughing… well, Sasuke laughed and Itachi chuckled. Itachi put Sasuke down and they both headed to the kitchen where Sasuke started preparing breakfast and Itachi watched as his brother cooked.

"Ne, Sasuke, when did you learn to cook?" he asked. Sasuke thought for a while, still working on the food.

"I guess when I was three, at Deadman Wonderland." He said. Itachi froze when he heard the name of the origin of his brother's torture. Sasuke seemed to sense his brother's discomfort and quickly changed the subject.

"Ne, nīsan, what do you want for breakfast?" he asked. Itachi thought for a while.

"Dango?" he asked. Sasuke laughed and nodded.

"Alright, I'll make you dango, but what should I make the others?" he asked.

"How 'bout Crepes?" Ken asked as he came into the kitchen. Sasuke nodded and started making the food.

{Ten minutes later}

"HOLY SH*T THIS IS F*CKING GOOD!" Hidan screamed as he shoved the rest of the crepe in his mouth. Sasuke sweat dropped and started eating his crepe at a slower pace. Itachi glanced at his brother, worried.

"Sasuke, are you sure you're going to be okay? What if your wound reopens?" he asked. Sasuke shook his head.

"Nīsan, it's already healed… I think." He said. Itachi immediately panicked and shook Sasuke back and forth.

"WHAT IF IT OPENS UP AGAIN?! YOU'LL DIE AGAIN SASUKE!" he screamed. Ken sighed and went to make some soup while the other members were busy gawking at the sight of a near hysterical Itachi. Sasuke sighed.

"Nīsan, I'll be fine. It's not like it's the first time it's ever happened." He said. Itachi froze and hugged Sasuke close to him.

"You'll never go through that ever again. I promise you that I'll protect you with my life." He said, having a major mood swing. Sasuke shook his head.

"Not with your life, nīsan. If you die, I'm going with you." He said stubbornly. Itachi's eyes widened and he shook his head furiously.

"Alright, not with my life. I'll do almost everything to protect you then." He said. Sasuke smiled and nodded.

"I'll protect nīsan too!" he said with a smile. Itachi smiled. Kisame sighed.

"Well, Sasuke, you'll have to work really hard to do that. Orochimaru is still after your brother." He said. Sasuke froze and turned to Kisame.

"Seriously?" he asked. Kisame nodded and Itachi looked worried while the others were waiting to see what Sasuke's reaction would be. And Ken was in the kitchen making soup for his dear Sasu-chan. A dark aura suddenly enveloped the room. Kisame's eyes widened when he saw the dark look in the young Uchiha's eyes as he cracked his knuckles.

"Tell me, are you guys trying to kill him?" he asked. The Akatsuki hesitantly nodded and watched as Sasuke's dark aura multiplied.

"Well then back off b*tches, this one's mine. He'll regret even looking at _**MY**_ nīsan." He said. Right when he said that, Ken walked into the room carrying a bowl of Misoshiru.

"Sasu-chan, your food's ready. Oh… what's wrong?" he asked. Sasuke turned to Ken, his dark aura increasing.

"Orosoontobedeadbastard decided that it would be fun to want my nīsan." He said. Ken nodded.

"Sucks to be him. I kinda feel bad for the guy, but he deserves it." He said. Sasuke nodded.

"You're d*mn right he does." He growled. Itachi chuckled nervously and patted his brother's head. Sasuke's aura immediately dissipated and he latched onto his brother.

"It's alright, otōto. You can kill him when you see him, but in order to do that, you need to eat and be healthy. How would you kill him if you're sick or injured?" he asked. Sasuke sighed and nodded.

"Fine. Snake bastard killing can wait." He said. Itachi chuckled at the name and pushed the bowl of Misoshiru in front of Sasuke, who just stared at it.

"Miso?" he asked. Ken nodded.

"Shiro or Aka?" he asked. Ken sighed.

"Aka." He said. Sasuke nodded and started eating along with everyone else. Once everyone was finished, Ken and Sasuke washed the dishes and they all went to the living room. Sasuke and Itachi were sitting on a couch together, Sasuke clinging to his brother.

"Ne nīsan, why did Konoha allow Deadman Wonderland to be created?" Sasuke asked. Itachi looked at him with sad eyes.

"I don't know, otōto." He said. Sasuke sighed.

"I don't understand. Did I do something wrong?" he asked. Itachi shook his head.

"You did nothing wrong, Sasuke. You never did." He said. Sasuke stared up at Itachi.

"Then why? I must've done something wrong. Was it because I'm an Uchiha?" he asked. Hidan sighed.

"Alright you little sh*t. I dunno what happened between you and the H*ll hole, but I'll tell you this. They have no f*cking brains. They only know how to f*cking kill people and torture their a**es off." He said, making Sasuke laugh. Itachi gave Hidan a grateful look and hugged Sasuke.

"Hidan is right. Don't let them get to you." He said. Sasuke nodded and smiled at Hidan.

"Hai. Arigato, Dan-chan." He said. Hidan looked confused.

"What the f*ck is a Dan-chan?" he asked. Sasuke giggled and pointed to him.

"Dan-chan is Dan-chan." He said, smiling. Hidan, finally getting the meaning, grimaced.

"Are you f*cking kidding me? Dan-chan sounds like an f*cking animal!" he whined. Kakuzu laughed at his partner and shook his head.

"Wow…" Ken said.

"I never knew that the day that Hidan got a pet name would ever come!" he squealed. Hidan glared.

"Shut the f*ck up you bastard!" he hissed, making Ken laugh harder. Sasuke tilted his head to the side innocently.

"Dan-chan doesn't like it?" he asked. Hidan immediately stopped swearing and stared at Sasuke, who looked like he was about to cry. Itachi gave Hidan a glare that clearly said 'make him cry and die', so Hidan decided to make Sasuke cry like the idiot he was.

"No I f*cking don't. I f*cking hate it and I hate you too you little sh*t." he said with a glare. Sasuke's lip trembled and a couple tears escaped.

"Why? Did I do something wrong?" he asked. Itachi immediately hugged his brother and wiped away the tears. Ken sighed and shook his head.

"Wrong choice Hidan. Sasu-chan is very shy and fragile. One wrong move will break him. Seems like you get to face the wrath of an extremely pissed off Uchiha." He said with a grin at the end. Hidan paled as Itachi turned to glare at him. Sasuke was still crying.

"Hidan…" Itachi growled. Hidan started stuttering and backed away slowly, but Itachi caught up to him faster and dragged him to the training grounds. Soon, Hidan's screams of pain and fear echoed throughout all the elemental countries. Kakuzu snickered at his idiotic partner's expense while Ken tried to get Sasuke to stop crying.

"Ne, Sasu-chan, stop crying… please?" he asked, but Sasuke's tears didn't stop. Ken tried a few more times before sighing and giving up.

"Alright, someone get him to stop crying. It's so heartbreaking!" he said. Sasori sighed and went over to Sasuke, placing a hand on his cheek. Sasuke looked up at him with a confused and hurt expression.

"Sasuke, stop crying. Hidan's an idiot. Just ignore him and his idiotic behavior. He just said what he said to annoy Itachi because he wanted to see his reaction to you crying." He said. Sasuke sniffled.

"Dan-chan wasn't lying though." He said. Sasori sighed.

"Look, just stop crying so your brother can stop killing Hidan. If Hidan dies by Itachi's hands, then Leader would punish Itachi. The punishment can be even worse than death." He said. Sasuke immediately stopped crying and rubbed his face, running to the training grounds to stop his Nīsan from killing Hidan and getting a punishment worse than death. Ken smiled and followed him.

"Arigato, Sasori-san." He said. Sasori nodded and sat back on the couch.

"D*MMIT! UCHIHA STOP F*CKING DECAPITATING ME!" Hidan's voice screamed.

"NĪSAN! DON'T KILL DAN-CHAN! PEIN-NĪ WILL KILL YOU!" Sasuke shouted. Itachi stopped killing Hidan and let Sasuke latch onto him.

"Nīsan, I dun' want you to get a punishment worse than death!" Sasuke whimpered. Itachi sighed and nodded.

"Fine. Hidan, be thankful that Sasuke was here to stop me." He said and left with Sasuke, leaving a decapitated Hidan lying on the ground.

"OI UCHIHA F*CKER! DON'T JUST LEAVE ME HERE!" Hidan screamed, but his screams fell on deaf ears. Itachi patted Sasuke's head.

"It's fine, just ignore him. He'll get over it." He said. The day was over and everyone was happy… well, almost everyone.

"OI! ANSWER ME D*MMIT! SOMEONE F*CKING PUT MY HEAD BACK ONTO MY F*CKING BODY!"

Owari. Chapter 5 'tis done. Dan-chan gets a pet name and pissed off 'Tachi-nī. He's really stupid…. Anyways, imōto-chan, don't be mad at me! I love Dan-chan too, but he pissed me off by acting like an a** and I had to do it! He's fine though! He always is. Ugh… imōto-chan… give me some ideas about how to string Pandora hearts into this. Should I like just slowly blend them together or should I just make a chappie where the Abyss just appears out of nowhere and Shiro Alice comes out and hurgs Sake-nī? It would be funny if that did happen, but it would be too sudden… and since the Abyss is owned by Kōri-chan, maybe she should visit Sake-nī and the others. She did say that Sake-nī had permission to use her powers since she shared with him… Holy crap that's a lot of words… Gomenasai…


	6. Chapter 6

Blood of the innocent chapter 6

Disclaimer: If I owned Naruto, then I wouldn't be writing fanfiction. I only own my OC's and my imōto-chan. I want to own Sake-nī and 'Tachi-nī, but life's too cruel to let me.

The day after Hidan's constant decapitation, Pein held a meeting concerning their goal and when to go get the bijū. Itachi patted Sasuke's head and smirked when Hidan glared at the older Uchiha. Sasuke stared at Hidan and hid behind his brother, pouting. Ken chuckled and looked at Hidan with a smug look.

"So, _Dan-chan_, did you enjoy your pain?" he asked, holding in his laughter. Hidan turned his glare onto Ken and scowled, flipping him off. Ken burst into laughter and ran out of the room. Pein sighed and rubbed his temples.

"Itachi, you and Kisame will go to Konoha to get the Kyūbi. Hidan and Kakuzu will get Nibi, and Tobi and Zetsu will go get Sanbi. Dismissed. Ah, Itachi, stay here. Sasuke can stay here if he wants to too." He said when Itachi stood up to leave with the others. Itachi nodded and sat back down with Sasuke on his lap. Once everyone else was gone, Pein closed the doors and sighed, looking at Itachi disapprovingly.

"Itachi, I know that Hidan isn't the most polite and chivalrous person out there, and that he has angered you by making your brother cry, but that's no excuse to continue decapitating him." He said, and right after that, there was a huge crash and Kakuzu's voice growled.

"HIDAN YOU IDIOT! DON'T GO BREAKING EVERYTHING IN THE BASE! DO YOU KNOW HOW MUCH THOSE COST?!" Pein stared at the doors and looked back at Itachi.

"I take that back. Decapitate him all you want. Just don't kill him. He's a valuable asset to the organization." He said. Sasuke giggled at Pein's decision and looked up at his brother. Itachi patted Sasuke's head and smiled.

"Hai. By the way, Pein-sama, when are we leaving to Konoha?" he asked. Pein nodded.

"You'll leave in a week." He said. Itachi nodded and stood up with Sasuke still in his arms. He bowed and walked out the doors and into the living room where Kakuzu had just decapitated his silver haired partner who was now cussing and screaming on the ground. Sasuke stared at Hidan's head and poked it when Itachi put him down. Hidan glared up at the young Uchiha, making him eep and hide behind Itachi. Ken, who was sitting on the couch reading, looked up from the scroll he was reading and almost had a spit take when he saw Hidan's head on the ground. He stared at the head in surprise and wonder.

"Woah… when did you get there?" he asked. Sasuke laughed and buried his face into his brother's stomach to muffle his laughter. Itachi smiled and gently hugged his brother back while all the other members stared at Ken with wide eyes.

"How can you _not_ notice him, un? He was screaming for like three hours straight, yeah." Deidara said, Kakuzu nodding in agreement.

"It's true." He said. Ken shrugged and went back to reading his scroll. Sasuke stared at his adoptive brother and giggled lightly, walking over to him quietly, cupping his hand around his ear, and made a very loud and painful popping noise with his tongue. Ken shrieked in surprise and fell off the couch with a thud. Sasuke fell over in a fit of giggles while the other members chuckled or burst into laughter. Itachi shook his head and picked up his baby brother, earning a small squeak of surprise. Sasuke stared at Itachi in surprise, but smiled and gave a small giggle. Kisame awed and patted Sasuke's head. Itachi smiled as Sasuke sneezed and shook his head furiously to fix his mussed up hair.

"Ne, Nīsan… why is everyone here being hunted down? When I went outside, I heard people saying that they needed to hunt down and capture the Akatsuki." Sasuke asked curiously. Ken sighed and looked to the young Uchiha.

"Sasu-chan, to Konoha and the other elemental countries other than Amegakure, the Akatsuki is a threat to them. Since the Akatsuki capture Jinchūriki and extract the bijū, they're a great threat to the countries with Jinchūriki." He said. Sasuke nodded and hugged his brother, nuzzling his cheek with his own. Itachi chuckled and hugged back his brother.

"Sasuke, you said that some people said that the Akatsuki needed to be hunted down." Itachi said, and at Sasuke's confirming nod, he continued.

"What did those people look like? Were they ninja?" he asked. Sasuke thought for a while.

"Ano… they had white masks with red squiggles on them, and there were little slits on the sides. I heard one of them say that they needed to get back to someone called… what was he called again? Ah! Kurogane Mana. Yeah, that's his name." he said. Itachi's eyes were wide and he quickly picked up his brother, running to Pein's office and barging in without knocking. Ken sighed and walked back to his room, leaving Itachi and Sasuke with a very pissed off Pein.

"What do you want Itachi?" he asked threateningly. Itachi didn't pay attention to his leader's anger and quickly explained everything.

"Pein, the Kurogane clan is planning to wipe out the Akatsuki. Their leader's name is Kurogane Mana. He's planning a full scale attack on us." He said. Pein's ringed eyes were wide with surprise and slight panic, which was really bad. Pein looked at Itachi impassively.

"Itachi, where did you get this information?" he asked. Itachi gestured to Sasuke, who was still clinging to his cloak shyly.

"Sasuke heard some of the Kurogane clan's shinobi talking." He said. Pein stared down at Sasuke.

"Are you sure that that's what they said? They weren't lying?" he asked. Sasuke shook his head.

"Mm. They said that Kurogane Mana-sama had better hurry up and destroy the Akatsuki or they'll die out or something like that. And then they said that the Akatsuki had to be destroyed." He said. Pein narrowed his eyes.

"Were they lying?" he asked. Sasuke shook his head.

"Iie. If they were, then they would've been dead right when they said that. Somehow, my eyes destroy people who lie too…" he said. Pein nodded gravely, still processing the new information. Finally, after five minutes of thinking, Pein looked to Itachi.

"Itachi, gather everyone. We're having a meeting." He said. Itachi nodded and led Sasuke out to the living room, where everyone was. When Itachi walked into the room, they all ignored him, but when he cleared his throat, all attention was turned to him.

"Pein-sama is calling a meeting. It is of upmost importance and holds the future of the Akatsuki." He said, walking to the meeting room and everyone else following him. In the meeting room, everyone got into their seats and waited for the meeting to start. Once everyone was present, Pein cleared his throat and began the meeting.

"Everyone, I have just received some grave news. The Kurogane clan is targeting the Akatsuki. Their leader is Kurogane Mana. We have to make a move before they do or the Akatsuki will seize to exist." He said. Everyone was surprised except for Itachi, Sasuke, Ken, and Deidara. The blond bomber looked confused.

"Who's Kurogane Mana, un?" he asked. It was Kakuzu who answered.

"Kurogane Mana was one of our members. He looked weak, but he was stronger than most of us. Right before you were forced to become a member, Mana quit and disappeared without a trace." He said. It made sense, but Deidara was still confused.

"Then why is he attacking the Akatsuki, hmm? And why did he quit, yeah?" he asked. Nobody knew the answer, so Sasuke answered.

"Kurogane Mana is a very selfish man. He joined the Akatsuki in order to fulfill his wish of becoming the king of the world. Mana committed various crimes such as rape, torture, murder, and many other crimes punishable by death. He quit the Akatsuki because he thought that you guys weren't giving him enough power. He joined because he thought that it was made for him by god. And he is attacking Akatsuki because he wants the bijū that you guys have captured. Oh, and the Kurogane clan doesn't really exist. It's just a group of twenty powerful nuke nin from various elemental countries." He explained in one breath. Everyone was surprised by his knowledge.

"How do you know all this squirt?" Kisame asked. Sasuke shrugged.

"I dunno. I just do." He replied casually. Kisame grinned, showing his pointed teeth.

"Glad you're deciding to open up to us." He said. Sasuke smiled shyly and hid behind his brother again. Kisame pouted.

"Awez… and you were doing so well." He said teasingly. Sasuke laughed lightly and stuck out his tongue. Itachi and Kisame chuckled at his behavior, but their laughter was short lived. An explosion shook the base and there was the sound of an army cheering. The Akatsuki all looked to each other and walked outside to see what was going on. When they got out of the base, they were all shocked at what they saw. A man with blood flowing down his hand was grinning at them. Beside him was a man with a white mask wearing a black overcoat. A young white haired girl with magenta eyes stood next to him. Sasuke's eyes widened at seeing them and his jaw dropped. Itachi was worried about his reaction and was about to console his brother, but Sasuke had disappeared. Hearing a grunt, Itachi looked forward and was surprised at the sight of Sasuke strangling the man who had an injured hand with the severity of his hug.

"Wah! Wei! Where were you?" he asked happily. Wei tried to push Sasuke off of him, but nothing worked.

"O-oi… I can't survive with no oxygen, Haruka." He managed to choke out. Sasuke looked up and saw that Wei was turning blue, so he quickly let go of him and let the man breathe. That was when Sasuke noticed the masked man standing next to him with a sweat drop going down his head. Sasuke grinned and tackled the poor guy in a bone crushing hug.

"Hei!" he said happily. Hei laughed nervously and patted Sasuke's back gently.

"Air, Haruka, air." He whispered. Sasuke pouted and let go of him, turning to look up at the girl.

"Ne, Yin, has Hei done anything weird?" he asked. Yin shook her head, her expression never changing from the usual emotionless façade.

"Iie." She said quietly. Sasuke huffed and then looked to everyone else who was standing either next to, or behind the two men.

"Ah, what are you guys doing here? And why did you blow up the base?" he asked curiously. Wei shrugged.

"We needed to get your attention and since we couldn't get in, we broke in." he said. Sasuke gave him a mock glare.

"You never 'broke' in. You broke the wall but you didn't come in." he mumbled. Itachi walked over to Sasuke and put a hand on his head.

"Otōto, who are these people?" he asked. Sasuke smiled.

"They're my family… kind of." He said. Amber, who was standing next to Wei, laughed.

"Haruka, still have your sense of humor I see." She said. Sasuke pouted.

"I never had a sense of humor. I don't even try to be funny and you guys laugh." He said, making Amber laugh again. Itachi looked confused, along with the rest of the Akatsuki minus Ken.

"What do you mean they're your family?" Kisame asked, walking next to Itachi. Amber smiled.

"He means exactly what he said. A few days after leaving that cursed h*ll, we found him close to our base. When we saw him, we instantly felt bad for him. He was just a child and he was forced to go through all that. So we all decided to help him. Of course, Ken helped, but he has absolutely no idea of how to take care of a child." She said. Kisame was still confused, so Amber explained even more.

"Basically, we found him severely injured in front of the EPR's base, so we decided to take care of him. But anyways, after about a year of taking care of him, we found out that he wasn't exactly what you would call human. He is one of us, a contractor. But he wasn't a contractor because he wanted to be. He was born one, which is really rare." She said. Itachi was shocked.

"So you're saying that _my_ baby brother is a contractor who _kills_ _people_ on his own free will?" he asked. Amber nodded sadly.

"I'm sorry to say that yes, he does kill on his own free will. But those that he kill are all sinners. All of them have committed crimes that would completely take away their humanity." She said. Wei, who was standing next to her, nodded in agreement.

"Yes, she is quite right. Though one thing was left out. Your brother, Sasuke, is not only born a contractor, but he is also the strongest contractor out of all of them. It's a surprise, actually, that such a small child would be submitted to such torture." He said regretfully. The Akatsuki were surprised now and Pein gestured to them.

"Let's go back in the base. We'll talk there." He said. They nodded and all walked into the base. In the living room, everyone got settled down. Partners shared the couches and Sasuke sat on Hei's lap, playing with his shirt with an innocent smile. Pein looked to Wei.

"You may begin." He said. Wei nodded, though he didn't like Pein's authoritative attitude.

"Well, like I said before, Sasuke is the strongest contractor. And because of that, he is always being chased by other contractors who want his power. Right now, Sasuke is ten, if I am correct." He said, looking to Sasuke for confirmation. Sasuke smiled and nodded.

"Mm! Ten." He said, giggling quietly before burying his face into Hei's chest, his small body shaking with silent laughter. Itachi and Ken were concerned.

"O-oi… Sasu-chan, you alright there?" Ken asked. Amber giggled.

"He's fine. I don't know why, but his age makes him laugh." She said with amusement. Itachi nodded and gestured for Wei to continue.

"Alright then. Continuing on, since Sasuke is always being chased for being the strongest, he is also very weak in a sense. He is injured easily, his wounds never heal in short periods of time, he is almost always is pain, and there are other things too. Like how after he uses his powers, he always ends up with a gaping hole in him and his personality turns into one of a doll. That's basically what happens to him just from using his power, so we forbid him from using it since it causes so much damage to himself." Wei said. Hei nodded.

"That's just the basics though. If you want a more detailed explanation, then you should ask Sasuke, though I doubt that he would tell you." He said. Hidan scowled.

"Why the f*ck not?" he asked, irritated. Hei sighed.

"Because, who would want to remember such horrifying events? Blood splattered everywhere, body parts strewn all over the place, and having severe injuries. That's what he has to go through." He said, though he quickly shut up when he remembered that he was holding onto Sasuke, who was shaking lightly and shaking his head.

"Sasuke? Sasuke, I'm sorry." Hei apologized, but Sasuke just kept on trembling, tears coming to his eyes and rolling down his pale cheeks.

"That happened? That's what always happens?" the young Uchiha asked shakily. Itachi stood up and walked over to his crying brother, picking him up and bouncing him gently.

"Shh… otōto, there's no reason to be afraid. It's the life of a shinobi. We all have to get used to it." He whispered. Sasuke didn't stop crying and buried his face into Itachi's neck.

"Nīsan…" he whimpered quietly. Itachi sighed, knowing how it felt to know that you've been killing people without knowing it. He hugged Sasuke tightly.

"It'll be alright, Sasuke. Didn't you hear what Hei-san said? All the people you've killed are sinners who's punishments would have been worse than death. You helped them, otōto." He said. That stopped Sasuke's tears and the child clung tightly to his brother, still not showing his face. Ken stayed silent, still digesting the new information.

"Wait a minute." He said. All heads turned to him.

"Sasu-chan has always been in Deadman Wonderland with me and some others until only recently. How could he have been with you guys too?" he asked. The Akatsuki were suspicious now, but Amber just smiled.

"It's easy, really. One of Sasuke's powers as a contractor is that he is able to make solid living clones of himself that only dispel when either he wants them to, or they die from natural causes or being killed." She said.

"He made one of them when he was in Deadman Wonderland and sent it to us. His clone told us that he would help us even if he wasn't with us." She finished. Itachi looked at his brother, who was still clinging tightly to him and patted his back gently.

"How? He's so young and he can barely hit someone without feeling guilty. How does he kill so many people and not break down?" Itachi asked. Wei answered that one.

"Hei explained it before. When Sasuke uses his powers, he not only gets injured, but his personality changes into that of a doll, meaning that he doesn't feel any pain. It also means that he does not have normal human emotions too, so he cannot feel regret or sadness." He said. Itachi saddened and held his brother up in front of him so he could see his face. Sasuke's normally cheerful face was now sad as he looked at his brother innocently.

"Nī?" he asked, as if he expected to be yelled at or hit. Itachi stared at Sasuke sadly before hugging him again.

"Sasuke, please don't use your powers again. I don't know what I would do if you were injured." He said sadly. The Akatsuki were pretty much used to Itachi's actions towards Sasuke and they nodded in agreement to Itachi's statement. Kisame stood up and walked over to the brothers, ruffling Sasuke's hair, smirking when he got a soft whine in response.

"It'll be alright squirt. Just don't use that power of yours and Itachi-san will be happy." He said with a grin. Sasuke looked up at Kisame and smiled cutely, earning an awe from the shark man. Sasuke pouted at the awe and buried his face into his brother's neck in an attempt to hide. Wei and Hei chuckled while Mao, the cat, flicked his tail and turned away. Amber giggled.

"Well, we'll leave you here to do your things. We'll be going back to our temporary hotel here." She said as she stood up with the others. They were about to leave, but Sasuke stopped them.

"Hei." He said quietly. The man turned to face him, a small smile on his face.

"Hai?" he asked. Sasuke looked at him worriedly.

"Hei, Pai said that she loves you." He said. Hei's eyes widened and then he smiled thankfully.

"Arigato, Sasuke." He said, leaving along with the others. Sasuke watched as they left and then buried his face into Itachi's neck once again. Itachi sensed his brother's sadness and sighed, patting his back gently.

"Sasuke?" he asked gently. Sasuke just shook his head softly.

"Nīsan, why am I a contractor? Am I a bad person?" he asked sadly, his voice slightly muffled due to his face being buried in his brother's neck. Itachi's eyes were wide with surprise and he quickly shook his head.

"Iie! Sasuke, I don't care what you are. You are my baby brother and I will always love you. Your choices will not affect my affection towards you." He said. Sasuke nodded and hugged Itachi tightly. Kisame awed and then went to his room to let the two brothers have their alone time. Soon, the rest of the Akatsuki minus Itachi and Sasuke all went back to their rooms as well. When the brothers were alone, Itachi hugged his brother tightly as he felt him tremble lightly.

"Sasuke, it's alright. Don't worry, otōto. Everything is going to be alright." He soothed. Hearing that, Sasuke started crying, tears falling onto Itachi's neck.

"Nīsan… I don't want to kill anybody anymore. Why can't everyone just get along?" he asked, hiccupping between his silent sobs. Itachi closed his eyes regretfully and placed his hand on his brother's head.

"Sasuke, that is not possible as of now. Humans are greedy, they are trash, tainted by their selfishness. There are only a few people in this world who care deeply about others and are willing to give their lives for the sake of others. A example would be Uzumaki Naruto." He said. Sasuke's tears didn't stop and he buried his face deeper into Itachi's neck.

"I… I don't like Konoha, nīsan." Sasuke said after a moment of silence. Itachi wasn't surprised, but decided to play along.

"Why?" he asked softly. Sasuke didn't lift his head.

"They're bad people. They made nīsan kill everyone. Now nīsan's the only Uchiha and it's all their fault that nīsan is alone." He said quietly. Now Itachi was surprised, though it was more like petrified.

"S-Sasuke, how do you know this? And what do you mean that I'm the only Uchiha? You're an Uchiha too!" he said. Sasuke shook his head.

"Nīsan, I was sent to Deadman Wonderland again because I knew of Danzō's plans. He didn't want me to be there to stop him, and it worked. It's my fault for not stopping him before hand. And I'm not an Uchiha. He said so. He did a blood test and he said that it came back negative. Nīsan isn't really nīsan then…" he said quietly, his voice shaking. Itachi's eyes were wide with surprise and anger now.

"Sasuke, why did you listen to him? He knows nothing but lies. You are an Uchiha. I was there in the hospital when Okāsan gave birth to you. They did a blood test then and it came back positive. Don't you ever say that I am not your brother, do you understand?" he asked, his voice stringed with anger. Sasuke stiffened and nodded slowly, scared that his brother was angry.

"H-hai… gomenasai, onīsama." He said obediently, all life gone from his voice. Itachi winced at Sasuke's voice and closed his eyes sadly.

"Gomenasai, otōto. I overreacted. Please forgive me." He said. Sasuke unburied his face and looked down.

"Hai, onīsama." He said, his voice still void of emotion. Itachi set Sasuke down and looked at him with concern, his eyes widening in horror when he saw Sasuke's eyes. Dull, void, empty, lifeless, like the eyes of a _doll_; Itachi thought about what Hei had told them while they were sitting with them.

_When he uses his power, he not only gets injured, but his personality also changes to that of a doll. He can feel no emotion, no pain, no nothing. The personality of a doll is like a void. Once you throw something at it, it will absorb the knowledge, but it will never use it. That is something that cannot be changed. If he ever changes into that without using his powers, call us immediately. We know what to do._

Itachi quickly made a clone and sent it to go get Hei. About two minutes later, his clone came back with the black haired man. At seeing Sasuke, Hei's expression darkened and he walked up to the child, kneeling down in front of him. Sasuke stared at him blankly, as if not recognizing him, but after staring at him for a while, Sasuke finally showed a form of reacting. His small ten year old hand slowly came up and grasped the fabric of Hei's shirt sleeve gently but tightly, and his dull, lifeless eyes stared into the dark eyes of the older contractor filled with an unknown emotion.

"Hei." Sasuke said quietly, his voice was flat. It was as if he was a robot, only knowing commands and not knowing how to use emotions in their voices. Hei looked at Sasuke sadly and patted his head.

"Sasuke, come back to us okay? You know how Amber reacts when she sees you like this." He said softly. This seemed to pull out a bit of Sasuke's emotions. His eyes flashed for a moment before going back to its usual dull void.

"Amber. Onēchan will be sad? Onēchan doesn't like me this way. Mm. Onēchan said so." He said quietly, his eyes brightening up a bit. Hei smiled and nodded.

"That's a good boy. Keep going at it. Remember Wei too, alright? He'll go berserk and blow holes in anyone and everyone who stands in his way to see you." He said with a small chuckle. Now Sasuke smiled, giggling lightly.

"Mm. Arigato, Hei." He said cutely, leaning up and kissing the contractor on the cheek. Hei was shocked, but soon smiled and ruffled the child's hair with a chuckle.

"Alright now. I'll take my leave. Take care." He said, disappearing. Itachi looked down at his baby brother worriedly, but was relieved when Sasuke smiled at him.

"Nīsan-" he started, but was cut off by an explosion outside the base. All the Akatsuki ran out of their rooms and out of the base to check what was going on, and they were surprised by Team 7, who was standing outside the base glaring at them.

"Give back Sasuke, dattebayou!" Naruto yelled, taking a step forward as he saw the young Uchiha standing with the Akatsuki. Sasuke winced at Naruto's loud voice and buried his face into his brother's chest, whimpering lightly. Itachi placed a hand on Sasuke's back and while glaring back at the blond Jinchūriki.

"What do you want?" he asked, his voice laced with hidden anger. Sakura stepped forward.

"We want you to return our teammate. Please, give him back!" she begged. Kisame took a step forward as well, grinning at the team.

"Well then, why didn't you come here before then?" he asked, confusing then team.

"What do you mean?" Kakashi asked, getting into a fighting stance. Kisame chuckled.

"When did you realize that the Sasuke on your team was a clone?" he asked. Team 7 gasped in shock at the news and Kisame frowned, sighing and shaking his head, then glaring at Tem 7 with hatred.

"You do not deserve to be his team." He growled. Kisame was about to attack, but he was stopped by a small hand tugging on his cloak. He looked down to see Sasuke staring up at him with a pleading expression on.

"Onegai…" he begged. "Don't tell them any more." Kisame sighed and forced himself to calm down, though he still shot hateful glares to Konoha's Team 7. Pein stared at the three ninja coldly and finally shook his head.

"Go back to Konoha and tell them to never mess with Akatsuki ever again. Unless you want your precious village to be destroyed, you would listen." He said calmly. Kakashi was furious and was about to attack, but was stopped by Naruto.

"Matte! What do you mean that the Sasuke on our team was a bunshin, dattebayou?" he asked. Ken sighed.

"I can't really blame the children for not knowing, but Kakashi, you should've been able to tell. How could you have let this poor child suffer by himself, all alone in this world, for almost his whole life?! He was looking up to you guys to save him from his torture, and yet, you ignored him! You ignored your promise to Obito!" he yelled. Kakashi took a step back, stunned and shocked at the same time, but Ken just continued.

"What happened to the 'I will never allow my comrades to die again'?! What happened to the shinobi that kept his promises? Are you really Kakashi or are you a clone too? Answer me!" he shouted. Kakashi looked to the ground guiltily.

"I… I-" he began, but was interrupted by Sasuke, who was crying silently.

"K-ken-nī… mou yamete. Don't tell them any more." He begged. Itachi wrapped an arm around his crying brother and picked him up. Sasuke stared at his brother sadly.

"Nīsan, will they go away?" he asked shakily. Itachi looked to the now petrified Team 7.

"Are you guys leaving now?" he asked. Naruto shook his head furiously.

"No! Not until I know what happened to Sasuke, dattebayou!" he yelled. Kisame sighed and looked to Sasuke.

"So squirt, do you trust them enough to tell them, or do you want us to force them to leave?" he asked. Sasuke shook his head.

"Shinjinai." He said quietly. "Karera wo shinjinai." Kisame grinned and slammed his sword into the ground.

"You heard the boy. Leave, or we'll make you." He said. Ken stood next to the shark man, taking out a kunai and cutting a small slit in his hand, letting his blood flow freely, becoming his weapon.

"You mess with him, you mess with us. Touch _our_ Sasuke and die." He growled protectively.

Well that was a stupid ending. Yay! More known about Sasu-chan!~ Well, I used Darker than Black in this one. I'm pretty sure that it sucked crap since I haven't been writing in a while, so feel free to yell my head off if you want. But please, nothing harsh enough to make me want to kill myself in my sleep. Oh, and I think my imōto-chan is coming in the next chapter… Just to clarify something that I thought of, this fanfiction doesn't just switch from one anime to another without leaving a trace of the other anime's I've used. Every time I add a new anime, which will probably be like four to five chapters each, I will also somehow cram in the other anime's, so by the end of this, our dear Sasu-chan will be a cute child that has gone through so much crap that's filled with many different powers from different anime's. Hope you like it.

I have a question for my dear, dear readers who waste their life to read my crap: What's good about this fanfic, what's bad about this fanfic, and how I can improve. It would be highly appreciated if authors or other fanfictions answered 'cause I can reply to them. Thanks!~


End file.
